Fluid exchange apparatus and methods

ABSTRACT

An injector apparatus comprises an elongate structure having one or more openings positionable near a penetrable barrier of an implantable device so as to receive fluid of the implantable device. The apparatus comprises a needle and a sheath extending over at least a portion of the needle. The elongate structure may comprise a distal tip to penetrate tissue and the penetrable barrier, and a distal opening near the tip to release therapeutic fluid into the implantable chamber. In many embodiments the distal tip, the distal opening, and the plurality of openings are separated from a stop that engages a tissue of the patient and limit penetration depth such that the distal opening and the plurality of openings are located along an axis of the implantable device to increase an efficiency of the exchange.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. application Ser.No. 13/615,229, filed Sep. 13, 2012, which claims priority of thefollowing U.S. Provisional Patent Applications: (1) U.S. ProvisionalApplication Ser. No. 61/535,900, titled, “Fluid Exchange Apparatus andMethods,” filed on Sep. 16, 2011; and (2) U.S. Provisional ApplicationSer. No. 61/595,604, titled, “Fluid Exchange Apparatus and Methods,”filed on Feb. 6, 2012. The disclosures of the Applications are herebyincorporated by reference in their entirety.

BACKGROUND

The present disclosure is generally directed to methods and apparatus toexchange a fluid of an implantable device.

Implantable devices can be used to provide a therapeutic agent to one ormore portions of a body of a patient. The implantable device may have achamber for storing the therapeutic agent, and the agent can be releasedinto the patient to provide a therapeutic benefit. After an amount oftime, the amount of fluid release can be less than ideal, and the fluidof the implantable device may be replaced, refilled, or exchanged toprovide additional amounts of therapeutic agent to extend the therapy.

Work in relation to embodiments of the present disclosure indicates thatthe prior methods and apparatus to place a fluid in a device implantedin the body can be less than ideal in at least some instances. Forexample, the amount of therapeutic fluid placed in an implantedtherapeutic device with injection can be less than ideal in at leastsome instances. The therapeutic fluid placed in the implantable devicemay mix with a fluid already present in the implantable device, suchthat the amount of therapeutic fluid placed in the implantable devicescan be less than ideal in at least some instances. Also, mixing of theimplantable device fluid with the therapeutic fluid during exchange canprovide a less than ideal sample of the fluid from the implantabledevice in at least some instances. At least some of the prior injectionsmay at least partially damage the implantable device, for example withrepeated injection of a needle through a septum. Further, as theimplantable device may be small, the amount of pressure within a chamberof the implantable device may substantially exceed atmospheric pressurein order to provide a clinically acceptable amount of time to place thetherapeutic fluid in the implanted device. In at least some instancesthe seal between the injector apparatus and implantable therapeuticdevice may be absent or inadequate and the exchanged fluids may leakfrom one or more of the injector apparatus or the implantable device inat least some instances.

Refilling devices implanted in the eye may present additional challengesin at least some instances. At least some of the prior devices implantedin the eye can be small to decrease interference with vision, and therefill port of such devices can be small and the eye can move rapidly inat least some instances. Alignment of the injection apparatus with therefill port of the implanted device can be more difficult than would beideal in at least some instances.

Work in relation to embodiments suggests that at least some priorinjector apparatus may be reused among patients, for example needles,and it may be helpful to limit reuse of the injector apparatus.

At least some of the prior methods and apparatus to diagnose a patienthave been less than ideal in at least some respects. In at least someinstances, the eye disease may have progressed more than would be ideal.Although tissue can be removed from the patient with a biopsy orvitreous humor removed with a vitreal tap, such procedures can be moreinvasive than would be ideal. It would be helpful to provide methods andapparatus to obtain a sample from a patient that is less invasive thanprior methods and apparatus.

SUMMARY

In light of the above, it would be desirable to provide improvedtreatments for the eye and improved methods and apparatus to placetherapeutic fluids in a device implanted in the eye. These treatmentsand methods and apparatus would decrease at least some of thedeficiencies of the prior art, and would provide improved replacementand sampling of a fluid of a device implanted within the body, improvedease of alignment, improved exchange efficiency, little or no leakageresulting from pressure of the injection, and a clinically acceptableexchange time.

Embodiments disclosed herein provide improved methods and apparatus totreat a patient having a device implanted in the body. The apparatus maycomprise an exchange apparatus having an elongate structure capable ofextending into the implantable device when implanted, and the elongatestructure may comprise an opening to place a therapeutic fluid in theimplanted device and one or more openings to receive an implantabledevice fluid from the implantable device. The implantable device maycomprise a lock, and the exchange apparatus may comprise a key, so as tolimit access to appropriate apparatus and formulations appropriate forthe implantable device. The implantable device fluid may comprise air,or a liquid such as saline or a fluid comprising a component of thepatient. The elongate structure of the exchange apparatus may comprise aneedle and a sheath, in which the sheath extends over a proximal portionof the needle so that the needle and the sheath can be advanced througha penetrable barrier and into a reservoir of the implantable device. Thesheath extending over at least a portion of the needle can maintainintegrity of the penetrable barrier, and can provide an outflow pathhaving a low resistance to flow so that the fluid within the implantabledevice can be displaced with decreased pressure. The outflow path canextend from the one or more openings to a receiver container configuredto receive the fluid of the implantable device. The implantable devicemay comprise a porous structure to release therapeutic agent for anextended time. The porous structure may comprise a resistance to fluidflow greater than the resistance to flow of the outflow path from theone or more openings to the receiver container, so that the fluid of theimplantable device can be displaced to the receiver container and flowthrough the porous structure inhibited. The exchange apparatus maycomprise a receiver container to receive a sample of the implantabledevice fluid when the therapeutic fluid is placed in the implantabledevice. In many embodiments, the exchange apparatus is configured toseparate at least a portion of the implantable device fluid from thetherapeutic fluid. The separation of at least a portion of theimplantable device fluid from the therapeutic fluid can provide a sampleof the implantable device fluid useful for analysis and may increase theamount of therapeutic fluid placed in the implantable device.

The one or more openings may comprise a plurality of openings to receivethe implantable device fluid. In many embodiments, an injector apparatuscomprises an elongate structure having a plurality of openingspositionable near a penetrable barrier of the implantable device so asto receive fluid of the implantable device and increase exchangeefficiency and decrease refill pressure. The elongate structure maycomprise a distal tip to penetrate tissue and the penetrable barrier,and a distal opening near the tip to release therapeutic fluid into theimplantable chamber. In many embodiments the distal tip, the distalopening, and the plurality of openings are separated from a stop thatengages a tissue of the patient and limits penetration depth such thatthe distal opening and the plurality of openings are located along anaxis of the implantable device so as to increase efficiency of theexchange. A tapered portion of the elongate structure can extend betweenthe distal opening and the plurality of openings so as to stretch apenetrable barrier when the elongate structure is advanced. Theplurality of openings can be located away from the tapered portion alonga proximal portion so as to maintain integrity of the penetrable barrierand so that leakage can be inhibited. The penetrable barrier can be usedrepeatedly with pressure for subsequent fluid exchange which can extendthe lifetime of the device implanted in the eye. The proximal portion ofthe elongate structure may comprise an extension without openingsextending from the stop to the plurality of openings so as to inhibitleakage through the penetrable barrier and place the plurality ofopenings away from a proximal side of the penetrable barrier. Theextension without openings may extend from the stop to the plurality ofopenings a distance corresponding substantially to a thickness of thepenetrable barrier, such that at least one of the plurality of openingsis placed near an inner surface of the penetrable barrier so as toreceive fluid near the surface of the penetrable barrier and increase anefficiency of the exchange. The plurality of openings can be distributedalong an axis of the elongate structure and may be distributedcircumferentially around the elongate structure so as to receive fluidfrom a plurality of axial and circumferential locations of the reservoirchamber of the implantable device.

The fluid initially within the implantable device may comprise a densityless than a therapeutic fluid, and the distal tip and plurality ofopenings can be configured to at least partially separate the fluidinjected through the distal tip from the fluid received through theplurality of openings. The distal opening may be placed below theplurality of openings so as to increase separation and the efficiency ofthe exchange. The distal opening can be placed below the plurality ofopenings with a distance from the stop shorter than a length of theimplantable device. The distance from the distal opening to the stop maycorrespond to a length of the reservoir chamber of the implantabledevice so as to position the distal tip having the opening near adistally located porous structure of the implantable device. In manyembodiments the distance from the distal opening to the stop can be nomore than about half the distance of the reservoir chamber of theimplant so as to facilitate alignment and provide high exchangeefficiency with the distal opening placed below the proximal pluralityof openings.

In many embodiments, the exchange apparatus comprises one or morestructures to separate at least a portion of the implantable devicefluid from the therapeutic fluid. The one or more structures maycomprise a valve, fluid separator, a separator fluid or combinationsthereof. The separator fluid may comprise a fluid miscible with thetherapeutic fluid and the implantable device fluid, or a fluidimmiscible with the therapeutic fluid and the implantable device fluidsuch as an immiscible fluid comprising one or more of an oil, ahydrophobic liquid, a gas, or air. The separator fluid can be containedin the fluid separator to inhibit mixing of the implantable device fluidwith the therapeutic fluid. The valve may be coupled to a first receivercontainer and a second receiver container such that a first portion ofthe implantable device fluid can be placed in the first containerwithout substantial amounts of therapeutic fluid. A second portion ofthe implantable device fluid mixed with the placed therapeutic fluid canbe placed in the second receiver container to inhibit mixing of thetherapeutic fluid with the sample contained in the first container. Thefluid separator may comprise a structure configured to contain theseparator fluid between the implantable device fluid and the therapeuticfluid to inhibit mixing.

While the elongate structure can be configured in many ways, in manyembodiments the elongate structure comprises a needle extending from theproximal stop to the distal tip and a sheath placed over the needle toprovide the plurality of openings and the tapered intermediate portion.The sheath may comprise a distal portion to engage the needle and anincreased cross sectional size to provide the taper. In many embodimentsthe sheath located over the needle provides one or more channels coupledto the plurality of opening to receive the fluid from the implantabledevice. The one or more channels may extend proximally from theplurality of openings to a container to receive the fluid from theimplantable device.

The exchange apparatus can be coupled to an injector in many ways andmay comprise an injector, such as a syringe. In many embodiments theexchange apparatus comprises a connector to couple to a syringe. Theconnector may comprise a known standard connector, such as a Luerconnector, or may comprise a custom connector, such as a keyedconnector, to inhibit inappropriate access to the implantable device.The connector may comprise a lock and key mechanism. The connector ofthe implantable device may comprise a lock and the connector of thesyringe may comprise a key to access the exchange apparatus.Alternatively, the injector can be integrated with the exchangeapparatus, and the injector may comprise an amount of therapeutic agentto inject into the implantable device.

In many embodiments, the receiver container comprises one or morechannels that vent to atmospheric pressure such that a gas within thereceiver container can be displaced with fluid comprising liquid fromthe implantable device. The receiver container may comprise a porousstructure that readily allows passage of the gas from the receivercontainer with a low resistance to flow and substantially inhibitspassage of the liquid from the implantable device chamber with asubstantially greater resistance to flow. The receiver container maycomprise a volume to inhibit re-use of the exchange apparatus, such thatthe injector apparatus can be a single-use device. The volume of thereceiver container may be no more than about twice a volume of thereservoir chamber of the implantable device, for example.

The container of the exchange apparatus can be configured to receive asample from the implantable device container, and to provide access tothe fluid stored in the receiver container. The fluid from the receivercontainer can be removed from the receiver container for analysis todetermine the health of the eye of the patient. The receiver containermay comprise a penetrable barrier to access the fluid sample within thereceiver container with a needle. The receiver container may beseparated from the exchange apparatus to provide the sample from thecontainer. Alternatively or in combination, the receiver container maybe pressurized to displace the sample fluid from the reservoircontainer.

In many embodiments, a sample container can be coupled to the receivercontainer so as to receive the implantable device fluid from thereceiver container. The exchange apparatus may comprise an elongatestructure having one or more openings to receive the implantable devicefluid, and the implantable device fluid can be displaced from thereceiver container so as to pass through the one or more openings andinto the sample container. The implantable device fluid can be displacedfrom the receiver container in many ways. A pressure source or a vacuumsource such as a syringe can be coupled to the one or more openings tourge the implantable device fluid from the receiver container to thesample container. The implantable device fluid can be urged, for exampledrawn, into the sample container with aspiration from the vacuum sourcecomprising the syringe. Alternatively or in combination, the implantabledevice fluid can be urged, for example pushed, with pressurization ofthe receiver container, for example from a pressure source comprising asyringe. A channel may extend from the receiver container to an openingthat vents to atmospheric pressure during exchange, and the opening canbe coupled to the syringe with pressurization subsequent to exchange,such that the channel and receiver container can be pressurized so as tourge fluid from the receiver container through the one or more openings.The receiver container and sample container may be placed in acentrifuge to urge implantable device fluid through the one or moreopenings onto an inner surface of the sample container. The samplecontainer may comprise a penetrable barrier such as a septum, and theelongate structure may be advanced to place the one or more openingswithin a chamber of the sample container such that the implantabledevice fluid can be displaced from the receiver container.

Additional aspects of the present disclosure are recited in the claimsbelow, and can provide additional summary in accordance withembodiments. It is contemplated that the embodiments as described hereinand recited in the claims may be combined in many ways, and any one ormore of the elements recited in the claims can be combined together inaccordance with embodiments of the present disclosure and teachings asdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an eye suitable for incorporation of the therapeuticdevice;

FIG. 2 shows a therapeutic device implanted under the conjunctiva andextending through the sclera to release a therapeutic agent intovitreous humor of the eye so as to treat the retina of the eye;

FIG. 3A shows an embodiment of a therapeutic device comprising acontainer having a penetrable barrier disposed on a first end, a porousstructure disposed on a second end to release therapeutic agent for anextended time;

FIG. 3B shows an embodiment of a porous structure comprising a pluralityof channels extending substantially straight through a disk;

FIG. 4 shows an embodiment of an apparatus to exchange fluid of a deviceimplanted in a an eye;

FIG. 5 shows an embodiment of an apparatus to exchange fluid coupled toan implanted device;

FIG. 6 shows an embodiment of an elongate structure of the apparatus toexchange fluid as in FIG. 5;

FIG. 7 shows a cross-sectional view of an embodiment of an elongatestructure of the apparatus exchange fluid comprising a sheath over aneedle;

FIG. 7A shows an embodiment of an exchange apparatus comprising alocking connector to couple to a syringe;

FIG. 7B shows an embodiment of an elongate structure and receivercontainer of the exchange apparatus of FIG. 7A;

FIG. 7C shows embodiments of sheaths suitable for combination with theexchange apparatus of FIGS. 7A and 7B;

FIG. 7D shows an embodiment of a sheath opening having a beveled channelsurface to inhibit degradation of the penetrable barrier;

FIG. 7E shows an embodiment of a sheath opening having a rounded channelsurface and edge to inhibit degradation of the penetrable barrier;

FIG. 7F shows an embodiment of schematic illustration of the pressuredrops across the porous structure and the one or more channels extendingfrom the plurality of openings to the receiver container;

FIG. 8A shows a cross-sectional view of an embodiment of the apparatusto exchange fluid as in FIGS. 5 and 6 coupled to a syringe;

FIG. 8B shows an embodiment of an implantable therapeutic devicecomprising a lock and an exchange apparatus comprising a key to thelock;

FIG. 8B1 shows an embodiment of a deflectable elongate structure in anunloaded configuration prior to insertion in the lock of FIG. 8B;

FIG. 8B2 shows an embodiment of a deflected elongate structure in anunloaded configuration prior to insertion in the lock of FIG. 8B;

FIG. 8C1 shows an embodiment of an implantable therapeutic devicecomprising a lock and an exchange apparatus comprising a rotatable keyto the lock;

FIG. 8C2 shows an embodiment of an implantable therapeutic device ofFIG. 8C1 in a locked configuration in which the elongate structureextends through the open lock to access the reservoir chamber of theimplantable device;

FIG. 8D1 shows an embodiment of an implantable therapeutic devicecomprising a lock and an exchange apparatus comprising a slidable key tothe lock;

FIG. 8D2 shows an embodiment of an implantable therapeutic device ofFIG. 8D1 in a locked configuration in which the elongate structureextends through the open lock to access the reservoir chamber of theimplantable device;

FIG. 8E shows an embodiment of an implantable therapeutic devicecomprising a lock and an exchange apparatus comprising an elongatestructure having engagement structures to open the lock;

FIG. 9 shows an embodiment of a container to receive and store theexchange apparatus;

FIG. 10 shows an embodiment of an exchange apparatus having a fluidsample within the receiver container;

FIG. 11 shows an embodiment of the exchange apparatus having the fluidsample placed partially within the storage container;

FIG. 12 shows an embodiment of a cap of the storage container placedover an outlet channel of the exchange apparatus to inhibit leakage;

FIG. 13 shows an embodiment of an elongate structure of the exchangeapparatus placed within a soft penetrable material near the bottom ofthe storage container and the cap placed over the container so as toseal the exchange apparatus within the container;

FIG. 14 shows an embodiment of an apparatus to remove the sample fluidfrom the receiver container;

FIG. 15 shows an embodiment of a cap placed on a connector to couple asyringe to the exchange apparatus;

FIG. 16 shows an embodiment of the exchange apparatus placed within areceptacle to couple the receiver container with a syringe to displacethe sample fluid from the receiver container into a sample container foranalysis;

FIG. 17 shows an embodiment of an exchange apparatus coupled to aremovable receiver container;

FIG. 18 shows an embodiment of the exchange apparatus coupled to animplanted device to exchange fluid and receive fluid from the implanteddevice;

FIG. 19 shows an embodiment of the exchange apparatus removed from theimplanted device and the receiver container detached from the exchangeapparatus;

FIG. 20A shows an embodiment of components of a container to remove asample fluid from an exchange apparatus;

FIG. 20B shows an embodiment of an exchange apparatus placed in thecontainer having components as in FIG. 20A;

FIGS. 20C and 20D show an embodiment of removal of a sample fluid froman exchange apparatus with the sample fluid drawn into the container asin FIG. 20B;

FIG. 21 shows an embodiment of a method of removal from an exchangeapparatus with a removal container as in FIGS. 20A to 20D;

FIG. 22 shows an embodiment of an exchange apparatus having a receivercontainer comprising a penetrable barrier on a side port to remove asample from the receiver container with a needle and syringe;

FIG. 23A shows an embodiment of an exchange apparatus having a receivercontainer coupled to a sample container and a syringe to displace fluidfrom the receiver container;

FIG. 23B shows the sample container of FIG. 23A placed over theplurality of openings of the exchange apparatus;

FIG. 24A shows an embodiment of an exchange apparatus having a receivercontainer coupled to a syringe with a sample container placed overopenings of the exchange apparatus so as to remove a sample from thereceiver container;

FIG. 24B shows an embodiment of the sample container of FIG. 24A placedover the plurality of openings of the exchange apparatus and the openingto the injection needle;

FIG. 25A shows an embodiment of an exchange apparatus comprising aremovable receiver container comprising a removable sheath placed over aneedle;

FIG. 25B shows an embodiment of the removable container of FIG. 25A witha plug placed over the sheath and the needle removed;

FIG. 25C shows an embodiment of the removable container of FIGS. 25A and25B with a plug placed over the sheath and a cap over the removablereceiver container;

FIGS. 26A, 26B, 26C, 26D and 26E show an embodiment of a centrifuge usedto remove the fluid sample from the receiver container of the exchangeapparatus;

FIG. 26F shows an embodiment comprising an exchange apparatus placed ina sample container comprising a centrifuge tube;

FIG. 26G shows an embodiment comprising an exchange apparatus placed ina sample container comprising a centrifuge tube, in which the centrifugetube comprises a support comprising a narrow shoulder portion of thetube to hold the exchange apparatus;

FIG. 26H shows an embodiment comprising an exchange apparatus placed ina sample container comprising a centrifuge tube, in which the centrifugetube comprises a support comprising restricted portion to hold theexchange apparatus;

FIG. 27A shows an embodiment of a collapsible fluid separator for usewith a therapeutic device;

FIG. 27B shows an embodiment of a plunger comprising an exchange needleand a shoulder suitable for use with the collapsible fluid separator asin FIG. 27A and a therapeutic device;

FIG. 27C shows an embodiment of the collapsible fluid separator as inFIG. 27B placed within a reservoir chamber of a therapeutic device;

FIG. 27D shows an embodiment of the plunger comprising the exchangeneedle and the shoulder as in FIG. 27B advanced into the access port ofthe therapeutic device having the collapsible fluid separator placedwithin the reservoir chamber of the therapeutic device as in FIG. 27C;

FIG. 27E shows an embodiment of the collapsible fluid separator advancedwithin the reservoir chamber of the therapeutic device as in FIG. 27D soas to displace the implantable device fluid from the reservoir chamberthrough the needle;

FIG. 27F shows an embodiment of the collapsible fluid separator advancedwithin the reservoir chamber to a location near the distal end of thereservoir chamber so as to displace most of the implantable device fluidfrom the reservoir chamber through the needle;

FIG. 27G shows an embodiment of the collapsible fluid separator movedfrom the distal end of the reservoir chamber so as to place therapeuticdevice fluid in the reservoir chamber;

FIG. 27H shows an embodiment of the collapsible fluid separator movedfrom the distal end of the reservoir chamber to the proximal end of thereservoir chamber so as to fill substantially the reservoir chamber;

FIG. 27I shows an embodiment of a substantially non-collapsible fluidseparator placed within a rigid walled container of a therapeutic devicehaving a substantially fixed cross sectional size;

FIG. 28A shows an embodiment of an exchange apparatus comprising aballoon supported on an elongate tubular member capable of introductioninto an implantable therapeutic device to exchange the implantabledevice fluid with a therapeutic fluid;

FIG. 28B shows an embodiment of the balloon as in FIG. 28A inflatedwithin the therapeutic device to displace the implantable device fluid;

FIG. 28C shows an embodiment of the balloon deflated within thetherapeutic device to provide space for the therapeutic fluid;

FIG. 28D shows an embodiment of the balloon punctured within thetherapeutic device to release the therapeutic fluid from the balloon tothe reservoir chamber of the therapeutic device;

FIG. 29A shows an embodiment of a deflectable fluid separator placedwithin an implantable therapeutic device;

FIG. 29B shows an embodiment of the deflectable fluid separator as inFIG. 29A displaced to a second side of the reservoir chamber to removefluid from the second side of the reservoir chamber;

FIG. 29C shows an embodiment of the deflectable fluid separator as inFIG. 29B displaced to a first side of the reservoir chamber with thetherapeutic fluid placed in the second side;

FIG. 30A shows an embodiment of an exchange apparatus comprising a valveto direct flow toward a second receiver container when a sample of theimplantable device fluid has been placed in a first receiver container;

FIG. 30B shows an embodiment of an exchange apparatus having a valvecomprising a porous structure to direct flow toward a second receivercontainer when a sample of the implantable device fluid has been placedin a first receiver container;

FIG. 30C shows an embodiment of an exchange apparatus having a floatvalve comprising a ball to direct flow toward a second receivercontainer when a sample of the implantable device fluid has been placedin a first receiver container;

FIG. 30D shows an embodiment of an exchange apparatus having a floatvalve comprising a sliding annular structure to direct flow toward asecond receiver container when a sample of the implantable device fluidhas been placed in a first receiver container;

FIG. 30E shows an embodiment of an exchange apparatus having a floatvalve comprising a flap to direct flow toward a second receivercontainer when a sample of the implantable device fluid has been placedin a first receiver container;

FIG. 31A1 shows an embodiment of an exchange apparatus having a fluidseparator comprising an internal channel sized to support theimplantable device fluid with a pocket of air;

FIG. 31A2 shows an embodiment of the exchange apparatus of FIG. 31A1having the implantable device fluid supported with a pocket of air toseparate the implantable device fluid from the therapeutic fluid;

FIG. 31B1 shows an embodiment of an exchange apparatus having a fluidseparator comprising an internal channel having a first portion sized tosupport the implantable device fluid with a pocket of air and a secondportion sized to pass air through the implantable device fluid;

FIG. 31B2 shows an embodiment of the exchange apparatus of FIG. 31B1having the first portion supporting the implantable device fluidcontained in the second portion with the pocket of air within the firstportion;

FIG. 31B3 shows an embodiment of the exchange apparatus of FIGS. 31B1and 31B2 having the first portion supporting the implantable devicefluid with the pocket of air and therapeutic fluid;

FIG. 31C shows an embodiment of an exchange apparatus coupled to asyringe to inject a displacement fluid comprising air into a therapeuticdevice to collect a sample of implantable device fluid;

FIG. 32 shows an embodiment of an exchange apparatus coupled to asyringe to draw therapeutic fluid into the implantable device withaspiration of the implantable device fluid into the syringe;

FIG. 33 shows an embodiment of a curved needle of an exchange apparatusto direct therapeutic fluid toward a wall of a container;

FIG. 34 shows an embodiment of a covering on a porous structure of atherapeutic device to inhibit bolus release when the therapeutic fluidis introduced and a needle of an exchange apparatus oriented toward thecovering;

FIG. 35 shows an embodiment of a first exchange apparatus coupled to adouble barrel syringe to exchange a first exchange fluid with theimplantable device fluid, and a second exchange apparatus to exchangethe first exchange fluid placed in the therapeutic device with atherapeutic fluid;

FIG. 36 shows an embodiment of an experimental test apparatus;

FIG. 37 shows experimental results obtained with the test apparatus ofFIG. 36.

DETAILED DESCRIPTION

Embodiments of the present disclosure as described herein can becombined in many ways to treat one or more diseases of a patient such asa disease of the eye. The embodiments as described herein are wellsuited to treat patients with a therapeutic agent for an extended time,such as may be provided with a device that can be at least partiallyimplanted into the eye. Although specific reference is made toophthalmic treatment of the eye, the methods and apparatus to place atherapeutic fluid in implantable device can be used with manyimplantable devices and treatments of one or more of many diseases, suchas systemic medication to treat systemic disease, orthopedic treatmentto treat orthopedic disorders, or dental treatment, for example. Theexchange apparatus and methods as described herein are well suited foruse with many drug delivery devices, such as refillable diffusion baseddevices, and can be exceptionally well suited for diffusion deviceshaving a porous drug release structure configured for extended releasein which the porous structure inhibits flow of fluid during exchange.

The exchange apparatus and methods as described herein are well suitedfor diagnoses and treatment of the eye, for example with diagnosis andtreatment of the eye based on the implantable device fluid received withthe exchange apparatus with the fluid is injected. The implantabledevice can be combined with one or more known methods of analysis ofbiomarkers, for example commercially available beads and arrays todetect and measure biomarkers. The methods and apparatus as describedherein are well suited for combination with analysis of samples asdescribed in U.S. Pat. App. Ser. No. 61/538,736, entitled “DiagnosticMethods and Apparatus”, Filed: Sep. 23, 2011, the full disclosure ofwhich is incorporated herein by reference. Examples of injectorapparatus, therapeutic devices, valves and mechanisms to provide thebolus injection are described in U.S. patent application Ser. No.12/696,678, filed on Jan. 29, 2010, entitled “Posterior Segment DrugDelivery”, Publication No. 2010/0255061; and U.S. PCT Pat. App. No.PCT/US2011/046812, filed Aug. 5, 2011, entitled “Injector Apparatus andMethod for Drug Delivery”, the entire disclosures of which areincorporated herein by reference. PCT Patent Application No.PCT/US2012/049654, filed Aug. 3, 2012 entitled “Small Molecule Deliverywith Implantable Therapeutic Device” is also incorporated herein byreference in its entirety.

As used herein like numerals and/or letters denote like elements in thedrawings and text as will be apparent to a person of ordinary skill inthe art.

FIG. 1 shows an eye 10 suitable for incorporation of the therapeuticdevice. The eye has a cornea 12 and a lens 22 configured to form animage on the retina 26. The cornea extends to a limbus 14 of the eye,and the limbus connects to a sclera 24 of the eye. A conjunctiva 16 ofthe eye is disposed over the sclera 24. A Tenon's capsule 17 extendsbetween the conjunctiva 16 and the sclera 24. The lens can accommodateto focus on an object seen by the patient. The eye has an iris 18 thatmay expand and contract in response to light.

The eye also comprises a choroid 28 disposed between the sclera 24 andthe retina 26. The retina comprises the macula 32. The eye comprises apars plana, which comprises an example of a region of the eye suitablefor placement and retention, for example anchoring, of the therapeuticdevice as described herein. The pars plana region may comprise sclera 24and conjunctiva 16 disposed between the retina 26 and cornea 12. Thetherapeutic device can be positioned so as to extend from the pars planaregion into the vitreous humor 30 to release the therapeutic agent. Thetherapeutic agent can be released into the vitreous humor 30, such thatthe therapeutic agent arrives at the retina 26 and choroid 28 fortherapeutic effect on the macula 32. The vitreous humor of the eye 30comprises a liquid disposed between the lens 22 and the retina 26. Thevitreous humor 30 may comprise convection currents to deliver thetherapeutic agent to the macula 32.

FIG. 2 shows a therapeutic device 100 implanted under the conjunctiva 16and extending through the sclera 24. FIG. 3A shows an exemplaryembodiment of the therapeutic device 100. The device 100 is configuredto release a therapeutic agent 110 into vitreous humor 30 of the eye 10so as to treat the retina of the eye. The therapeutic device 100 maycomprise a retention structure 120 such as a smooth protrusionconfigured for placement along the sclera 24 and under the conjunctiva16, such that the conjunctiva 16 can cover and protect the therapeuticdevice 100. When the therapeutic agent 110 is inserted into the device100, the conjunctiva 16 may be lifted away, incised, or punctured with aneedle to access the therapeutic device 100. The eye 10 may comprise aninsertion of the tendon of the superior rectus muscle to couple thesclera of the eye to the superior rectus muscle. The device 100 may bepositioned in many locations of the pars plana region, for example awayfrom tendon and one or more of posterior to the tendon, anterior to thetendon, under the tendon, or with nasal or temporal placement of thetherapeutic device.

While the implant can be positioned in the eye in many ways, work inrelation to embodiments suggests that placement in the pars plana region25 can release therapeutic agent into the vitreous 30 to treat theretina 26, for example therapeutic agent comprising an active ingredientcomposed of large molecules.

Therapeutic agents 110 suitable for use with device 100 include manytherapeutic agents, for example as listed in Table 1A, herein below. Thetherapeutic agent 110 of device 100 may comprise one or more of anactive ingredient of the therapeutic agent, such as a formulation of thetherapeutic agent, a commercially available formulation of thetherapeutic agent, a physician prepared formulation of therapeuticagent, a pharmacist prepared formulation of the therapeutic agent, or acommercially available formulation of therapeutic agent having anexcipient. The therapeutic agent may be referred to with generic name ora trade name, for example as shown in Table 1A.

The therapeutic device 100 can be implanted in the eye to treat the eyefor as long as is helpful and beneficial to the patient. For example thedevice can be implanted for at least about 5 years, such as permanentlyfor the life of the patient. Alternatively or in combination, the devicecan be removed when no longer helpful or beneficial for treatment of thepatient.

The therapeutic agent 110 can be placed in the therapeutic device 100 inmany ways. In many embodiments, a therapeutic fluid 260 (FIG. 2)comprising therapeutic agent 110 is exchanged with an implantable devicefluid 262 contained within therapeutic device 100, as shown in FIG. 2.An exchange apparatus 200 can be configured to place the therapeuticfluid 260 and to receive the implantable device fluid displaced from theimplantable device when the therapeutic fluid is placed.

With reference to FIG. 2, an exemplary embodiment of the exchangeapparatus 200 comprises an elongate structure 201 that can be placedsubstantially within the implantable device. The elongate structure 201comprises an opening to place the therapeutic fluid in the reservoirchamber of the implantable device and one or more openings to receivethe implantable device fluid from the reservoir chamber. The exchangeapparatus 200 may comprise the therapeutic fluid 260 and the receivercontainer 250 to receive fluid 262 of the implantable device. Thetherapeutic device 100 may comprise a reservoir chamber to store anamount of the therapeutic agent 110. The reservoir chamber may comprisea fluid 262 of the implantable device 100. The fluid 262 of theimplantable device can be displaced when the therapeutic fluid 260 isinjected, for example, and a receiver container 250 can be provided toreceive the implantable fluid 262 from the implantable device. Thereservoir chamber of the implantable device may comprise a substantiallyrigid walls and a substantially fixed volume, for example.

The exchange apparatus 200 can be configured in many ways, and may becoupled to a syringe 300 with one or more of many connectors, such as aLuer connector, a Luer-Lok™ connector, for example. Alternatively or incombination, the exchange apparatus may comprise syringe 300, forexample. The exchange apparatus 200 may comprise an elongate structure201 to for insertion into the reservoir chamber of the implantabledevice, and a stop 240 to limit a depth of insertion of the elongatestructure 201 into the reservoir chamber of the implantable device. Theexchange apparatus 200 may comprise a receiver container 250 to receivethe implantable device fluid from the reservoir chamber of theimplantable device, and the elongate structure may comprise a pluralityof openings coupled to the receiver container so as to receive the fluidof the implantable device through the plurality of openings when thefluid is injected. Alternatively, the therapeutic fluid may be drawninto the reservoir chamber of the implantable device with aspiration ofthe implantable device fluid into chamber 310 of the syringe, such thatthe therapeutic fluid placed in chamber 250 can be drawn into thereservoir chamber of the implantable device, for example.

FIG. 3A shows a therapeutic device 100 comprising a container 130 havinga penetrable barrier 184 disposed on a first end, a porous structure 150disposed on a second end to release therapeutic agent for an extendedperiod, and a retention structure 120 comprising an extension protrudingoutward from the container to couple to the sclera and the conjunctiva.The container 130 may comprise an axis 100A. The inner surfaces of thecontainer 130 may define a reservoir chamber having a volume sized toprovide therapeutic amounts of the therapeutic agent for the extendedtime. The extending protrusion of the retention structure may comprise adiameter 120D. The retention structure may comprise an indentation 120Isized to receive the sclera.

The container may comprise a tubular barrier 160 that defines at least aportion of the reservoir, and the container may comprise a width, forexample a diameter 134. The diameter 134 can be sized within a range,for example within a range from about 0.5 to about 4 mm, for examplewithin a range from about 1 to 3 mm and can be about 2 mm, for example.The container may comprise a length 136 sized so as to extend from theconjunctive to the vitreous along axis 100A to release the therapeuticagent into the vitreous. The length 136 can be sized within a range, forexample within a range from about 2 to about 14 mm, for example within arange from about 4 to 10 mm and can be about 7 mm, for example. Thevolume of the reservoir may be substantially determined by an innercross sectional area of the tubular structure and distance from theporous structure to the penetrable barrier. The retention structure maycomprise an annular extension having a retention structure diametergreater than a diameter of the container. The retention structure maycomprise an indentation configured to receive the sclera when theextension extends between the sclera and the conjunctive. The penetrablebarrier may comprise a septum disposed on a proximal end of thecontainer, in which the septum comprises a barrier that can bepenetrated with a sharp object such as a needle for injection of thetherapeutic agent. The porous structure may comprise a cross sectionalarea 150A sized to release the therapeutic agent for the extendedperiod.

The porous structure 150 may comprise a control release mechanism. Theporous structure 150 can be configured in many ways to providecontrolled sustained release, for example with a release rate index, ora size and number of openings, for example. The porous structure 150 maycomprise a first side 150S1 coupled to the reservoir and a second side150S2 to couple to the vitreous. The first side may comprise a firstarea 150A1 and the second side may comprise a second area 150A2. Theporous structure may comprise a thickness 105T. The porous structuremany comprise a diameter 150D.

The porous structure 150 may comprise one or more of a release controlelement, a release control mechanism, permeable membrane, asemipermeable membrane, a material having at least one hole disposedtherein, channels formed in a rigid material, straight channels,nano-channels, nano-channels etched in a rigid material, laser drilledholes, laser etched nano-channels, a capillary channel, a plurality ofcapillary channels, one or more tortuous channels, sintered material,sintered rigid material, sintered glass, sintered ceramic, sinteredmetal, tortuous micro-channels, sintered nano-particles, an open cellfoam or a hydrogel such as an open cell hydrogel. Additional examples ofporous structures are described in U.S. patent application Ser. No.12/696,678, filed on Jan. 29, 2010, entitled “Posterior Segment DrugDelivery”, Publication No. 2010/0255061; and U.S. PCT Pat. App. No.PCT/US2011/046812, filed Aug. 5, 2011, entitled “Injector Apparatus andMethod for Drug Delivery”, the entire disclosures of which have beenpreviously incorporated herein by reference.

The volume of the reservoir chamber may comprise from about 5 μL toabout 2000 μL of therapeutic agent, or for example from about 10 μL toabout 200 μL of therapeutic agent. The reservoir may comprise an axiallength 136C extending between the penetrable barrier 184 and the porousstructure 150.

The therapeutic agent stored in the reservoir of the container comprisesat least one of a solid comprising the therapeutic agent, a solutioncomprising the therapeutic agent, a suspension comprising thetherapeutic agent, particles comprising the therapeutic agent adsorbedthereon, or particles reversibly bound to the therapeutic agent. Forexample, reservoir may comprise a suspension of a cortico-steroid suchas triamcinolone acetonide to treat inflammation of the retina. Thereservoir may comprise a buffer and a suspension of a therapeutic agentcomprising solubility within a range from about 1 μg/mL to about 100μg/mL, such as from about 1 μg/mL to about 40 μg/mL. For example, thetherapeutic agent may comprise a suspension of triamcinolone acetonidehaving a solubility of approximately 19 μg/mL in the buffer at 37° C.when implanted.

The release rate index may comprise many values, and the release rateindex with the suspension may be somewhat higher than for a solution inmany embodiments, for example. The release rate index may be no morethan about 5, and can be no more than about 2.0, for example no morethan about 1.5, and in many embodiments may be no more than about 1.2,so as to release the therapeutic agent with therapeutic amounts for theextended time. The release rate index can be at about 0.01, for example.

The therapeutic device, including for example, the retention structureand the porous structure, may be sized to pass through a lumen of acatheter.

The porous structure may comprise a needle stop that limits penetrationof the needle. The porous structure may comprise a plurality of channelsconfigured for the extended release of the therapeutic agent. The porousstructure may comprise a rigid sintered material having characteristicssuitable for the sustained release of the material.

FIG. 3B shows a porous structure comprising a plurality of substantiallystraight channels 150SC extending substantially straight through a disk.The channels 150SC can extend from a first side 150S1 to a second side150S2 a distance comprising thickness 150T of the porous structure. Eachof the channels comprises a cross-sectional dimension across, forexample a diameter, and a corresponding area across the cross section.The combined cross-sectional area of the plurality of channels, thethickness 150T, the diffusion coefficient of the therapeutic agent, theconcentration of therapeutic agent within the reservoir chamber and thevolume of the reservoir chamber determine substantially the release rateprofile of the therapeutic agent. The size and number of the pluralityof channels 150SC and thickness of the porous structure can beconfigured so as to provide the release rate profile.

The porous structure 150 may comprise the control release mechanismhaving one or more straight channels 150SC through which material (e.g.,fluid that contains therapeutic agent) can pass. There can be at least3, for example at least 6 and even more typically at least 10 channels.There may be fewer than 1000 channels, for example no more than 200 andin many embodiments no greater than 50 of the channels 150SC.

Material, particularly ophthalmic pharmaceutical composition and aqueoushumor fluid, is typically allowed to freely flow and/or diffuse into andout of the reservoir chamber 140 (FIG. 3A) with the size of the openingsof channels 150SC assisting in controlling the rate of flow and/ordiffusion into and out of the reservoir chamber 140. The openings of theplurality of channels 150SC, particularly for a passive system, have across-sectional area that controls the rate at which material,particularly therapeutic agent, flows out of the reservoir and into theeye. That cross-sectional area can be at least 8 μm², more typically atleast 15 μm² and even more typically at least 50 μm². That samecross-sectional area can also be no greater than 4000 μm², for exampleno greater than 2000 μm² and in many embodiments no greater than 500μm². The cross-sectional area of the opening may comprise any sectionalarea of the opening wherein the outer perimeter of the opening is fullydefined by the material of the control release mechanism and wherein,for fluid to pass through the opening into or out of the reservoirchamber 140, it also passes through the cross-sectional area.

In the illustrated embodiments, as shown in FIG. 3B, the porousstructure 150 comprising the control release mechanism can be a plate150PL. The plurality of channels 150SC extends through the plate 150PL.The plate 150PL may have opposing substantially parallel surfacesthrough with the channels extend to the opening on each surface. In theembodiments shown, the channels 150SC are cylindrical shape althoughthey may be shaped otherwise as well. The channels 150SC may have adiameter of at least about 0.2 microns, for example at least about 2microns and in many embodiments at least about 8 microns. The diameterof the openings may be no greater than about 100 microns, for example nogreater than 40 microns and in many embodiments no greater than about 25microns. While it is understood that a generally uniform distribution ofthe openings over the surface of the plate 150PL is desirable, othernon-uniform distribution of opening the openings are also possible. Asuitable thickness for the plate will typically be at least about 0.05mm, more typically at least about 0.08 mm and will typically no greaterthan 0.5 mm and more typically no greater than 0.3 mm.

The porous structure 150 comprising the control release mechanism maycomprise a plate 150PL. The plate 150PL may be formed of a variety ofmaterials such as metals or polymeric materials. In many embodiments,the plate 150PL is formed of an etchable material such as silicon, whichallows the channels 150SC to be etched into the material.

The number and size of each of the openings provides a combinedcross-sectional surface area for the plate 150PL. The combinedcross-sectional surface area of the channels 150SC may be no more thanabout 100,000 μm², so as to provide sustained release of the therapeuticagent for an extended time. While the combined cross-sectional surfacearea can be within a range from about 1000 μm² to about 100,000 μm², inmany embodiments the combined cross-sectional area is within a rangefrom about 2,000 μm² to about 30,000 μm², for example about 2,000 toabout 10,000 μm². The combined cross-sectional area can be determinedbased on one or more of the thickness of the plate 150PL, the diffusioncoefficient of the therapeutic agent, the volume of the reservoirchamber, the concentration of the therapeutic agent placed in thereservoir chamber, or the targeted release rate profile of thetherapeutic agent above a minimum inhibitory concentration for apredetermined amount of time, or combinations thereof, for example.

FIG. 4 shows an exemplary apparatus 200 to exchange fluid of a deviceimplanted in an eye. The apparatus 200 may comprise or be coupled to asyringe 300 to inject a therapeutic fluid comprising a therapeutic agentin to the device implanted in the eye. The apparatus 200 comprise anelongate structure 201 comprising a distal portion 210, and intermediateportion 220 and a proximal portion 230. The elongate structure 201extends along an axis 202 from a stop 240 to position the distal portion210, the intermediate portion 220, and the proximal portion 230corresponding locations of the reservoir chamber. The distal portion 210comprises a distal tip 212 to penetrate tissue and the penetrablebarrier of the implantable device and an opening 214 to injecttherapeutic fluid into the implantable device. The intermediate portion220 comprises a tapered section 224 to gradually increase a size of thechannel formed in the penetrable barrier when the needle is advancedthrough the penetrable barrier, so as to maintain integrity of thepenetrable barrier and inhibit damage to the penetrable barrier. In manyembodiments, the tapered portion 224 may extend along axis 202 withoutholes so as to decrease pressure to the penetrable barrier that mayotherwise occur near the edge of a hole. The proximal portion 230 maycomprise a plurality of openings 236 to receive the fluid from thereservoir chamber of the implantable device. The proximal portion 230may comprise an extension 238 extending from the stop 240. The extension238 may extend from the stop 240 without holes to inhibit leakage whenthe fluid is exchanged and the stop 240 engages the conjunctiva.

FIG. 5 shows the apparatus 200 coupled to an implantable device 100. Thestop 240 is positioned to engage the conjunctiva 16, and the elongatestructure 201 extends through the conjunctiva 16 and penetrable barrier184 into the reservoir chamber 140 of the implantable device 100 whenthe apparatus 200 is coupled thereto. The elongate structure 201 can besized so as to place distal tip 212 at a location within the reservoirchamber of the implantable device when the surface of the stop contactsthe conjunctiva, for example. The distal tip 212 can be located onelongate structure 201 so as to place the distal tip 212 at a locationfrom the penetrable barrier within implantable device 100 that is nomore than a desired length, such as about ¾ of the length 136 of theimplantable device, and in some embodiments no more than about half ofthe distance 136C of the reservoir chamber. The plurality of openings236 is located near the penetrable barrier 184 so as to receive fluidcontacting the reservoir chamber. The extension 238 extendssubstantially through the penetrable barrier 184, for example at leastabout half way through the penetrable barrier so as to position theplurality of openings away from an external surface of the penetrablebarrier and to inhibit leakage.

FIG. 6 shows an enlarged view of the elongate structure 201 of theapparatus 200. The elongate structure 201 extends along axis 202 betweenthe distal tip 212 and stop 240. The distal portion 210 may comprise anextension 211 having a substantially constant cross-sectional sizeextending between the tip 212 to penetrate tissue and the intermediateportion 220. In many embodiments, the extension 211 comprises a portionof a needle 270 extending between the stop 240 and the tip 212 topenetrate tissue, which tip may comprise the tip of the needle topenetrate conjunctival tissue.

The tip to penetrate tissue 212 and the opening 214 can be located adistance 204 from the stop and the plurality of opens to provideefficient exchange of the fluid within the reservoir chamber of theimplanted device. In many embodiments, the opening 214 is placed withinthe reservoir chamber at a distance from the stop 240 greater than theplurality of openings 236 to inhibit mixing of the injected therapeuticfluid with the fluid within the reservoir chamber of the implanteddevice. The opening 214 can be separated from the plurality of openingswith a distance 208, such that the opening 214 can be located below theplurality of openings when the therapeutic fluid is injected.

The therapeutic fluid may comprise a density greater than the fluid ofthe implanted device and opening 214 can be placed below the pluralityof openings 236 when the therapeutic fluid is injected to inhibitmixing. The axis 100A (see FIG. 3A) of the implantable device and thecorresponding axis of the reservoir chamber can be oriented away fromhorizontal, such that porous structure 150 may be located below thepenetrable barrier 184 when the therapeutic fluid is injected. The axis202 can oriented away from horizontal such that opening 214 can beplaced below the plurality of openings 236. The therapeutic fluidcomprising the greater density can flow toward the distal end of thetherapeutic device and the displaced fluid of the implantable devicehaving the lesser density can be received by the plurality of openings236 located above the opening 214.

Examples of therapeutic agents and corresponding formulations and fluidsthat may have a density greater than the density of the fluid within thechamber of the implanted device are listed in Table 1A. For example, oneor more of the therapeutic agent or a stabilizer can increase thedensity of the therapeutic fluid. In many embodiments the therapeuticfluid having the greater density comprises a stabilizer, such astrehalose, and the therapeutic agent such as a protein comprising anantibody fragment. Alternatively or in combination, the therapeuticformulation may comprise an amount of therapeutic agent sufficient toprovide a density greater than the fluid of the implanted device. Thedifference in density can be within a range from about 1% to about 10%and can depend on the density of the fluid within the reservoir chamberof the therapeutic device and density of the therapeutic fluid placed inthe reservoir chamber with the exchange apparatus. The density of thetherapeutic fluid may correspond to a density of the therapeutic agentand a density of the stabilizer (when present). In many embodiments, thedensity of the fluid of the reservoir chamber may correspond to adensity of phosphate buffered saline, or plasma, or an amount oftherapeutic fluid remaining in the reservoir from a prior exchange, orcombinations thereof, for example.

When injected into a device implanted within the patient, the distance204 may correspond to no more than approximately the distance of thereservoir chamber of device 140. The distance 204 may correspondsubstantially to the length of the reservoir chamber so as to place thedistal tip near the porous structure, and the elongate structure of theexchange apparatus can be aligned with an elongate axis of theimplantable device. In many embodiments, the distance 204 may correspondto no more than about half the distance of the reservoir chamber, suchthat the elongate structure 201 can be readily aligned with theimplantable device. Work in relation to embodiments suggests than adistance providing a tolerance for angular alignment error of the axis100A with the axis 202 can facilitate exchange and improve efficiency ofthe exchange. The distance 204 from stop 240 to tip 212 comprising nomore than about half of the axial distance of the implantable device canfacilitate alignment during injection.

The intermediate portion 220 may comprise an extension 222 extendingbetween tapered portion 224 and the distal portion 210. The extension222 may comprise a cross-sectional size that is smaller than the taperedportion 224. The extension 222 may comprise a smooth outer surface topenetrate tissue. The tapered portion 224 may comprise a smother outersurface to penetrate tissue and the penetrable barrier. The outersurface of the tapered portion can extend at an angle of inclinationrelative to the axis, and the tapered portion 224 may comprise a conicsection having an angle with the axis such that the outer surfaceextends at the angle of inclination relative the axis. The angle ofinclination of the tapered portion 224 can be no more than about 25degrees, for example. The angle of inclination can be about 1 degree,about 2 degrees, about 5 degrees, about 10 degrees, about 15 degrees,about 20 degrees, or about 25 degrees, for example. The extensionportion 216 may comprise a first cross-sectional dimension, and theportion having the plurality of openings may comprise a second crosssectional dimension greater than the first dimension, such that taperedportion having the angle of inclination extends there between to connectthe extension portion 216 with the portion having the plurality ofopenings 236.

The proximal portion 230 may comprise the plurality of openings 236spaced apart along the axis 202 and distributed circumferentially aroundthe proximal portion to receive fluid from a plurality ofcircumferential and axial locations when the stop 240 engages theconjunctiva to place the plurality of openings within the reservoirchamber. At least one 237 of the plurality of openings can be separatedfrom the stop 240 with a distance 206 corresponding substantially to thethickness of the penetrable barrier 184, such that the at least one 237of the plurality of openings 236 can be placed near the inner surface ofthe penetrable barrier to receive fluid contacting the inner surface ofthe penetrable barrier. In many embodiments, the thickness of thepenetrable barrier is within a range from about 0.25 to about 2 mm, forexample within a range from about 0.5 to about 1.5 mm, such that thethickness of the penetrable barrier is substantially greater than athickness of the conjunctiva which can be approximately 100 μm. Thedistance 206 corresponding substantially to the thickness of thepenetrable barrier may correspond substantially to the thickness of thepenetrable barrier and the epithelium of the patient.

A sheath 280 can be configured to extend over at least a portion ofneedle 270. The sheath 280 may extend along the intermediate portion 220and the proximal portion 230, and the needle 270 can extend through thesheath. The sheath 280 may comprise the plurality of openings 236 andprovide one or more channels extending along needle 270 to pass thefluid of the implantable device through the septum.

The sheath 280 may comprise portions corresponding to the intermediateand proximal portions of the elongate structure 201. The extension 222may comprise a distal portion sheath 280 having an inner surface sizedto engage an outer surface of the needle, and the diameter of theportion to engage the needle may comprise an inner cross sectionaldiameter less than the needle to engage the needle with at least one orof pressure or friction. The tapered portion 224 may comprise anintermediate portion of sheath 280, in which the sheath 280 comprisestapered surface to penetrate the tissue and penetrable barrier 184. Theproximal portion 230 may comprise a proximal portion of the sheath 280comprising the plurality of openings 236 and the extension 238. Achannel 239 can extend along an outer surface of the needle to theplurality of openings 236. The channel 239 can extend proximally alongextension portion 238 toward a container 250 (see FIG. 8A) to receivethe fluid of the implantable device. The channel 239 may couple theplurality of openings to the container to receive the fluid of theimplantable device.

FIG. 7 shows a cross-sectional view of an elongate structure of theapparatus exchange fluid comprising the sheath 280 over the needle 270.The needle may comprise channel 219, for example a lumen, extendingdistally to the opening 214 (see FIG. 6) and proximally to a connectorto couple the channel 219 to a syringe, for example. A wall 252 ofcontainer 250 comprises sufficient strength to resist deformation whenthe stop 240 engages the tissue, and the stop 240 may comprise adeformable stop to couple to the tissue (see FIG. 8A). An outlet channel254 extends from container 250 to at least one vent opening 258 toatmospheric pressure (see FIG. 8A).

FIG. 7A shows an exchange apparatus comprising a locking connector tocouple to a syringe. The connector 290 may comprise a locking connectorhaving an extension 292 sized to fit in a channel of connector 320 ofsyringe 300, for example (see FIG. 8B). The exchange apparatus 200 maycomprise components of a standard locking needle assembly, for example astandard locking needle such as a Luer-Lok™ fitting. The wall 252 thatdefines container 250 and sheath 280 can fit over the needle 270 whichmay comprise a standard needle assembly. The wall 252 can extend asubstantial distance from stop 240 to opening 258, for example, so as todefine container 250 and channel 254 extending between the lockingneedle assembly and the wall.

FIG. 7B shows the elongate structure 201 and receiver container 250 ofthe exchange apparatus 200 of FIG. 7A. The wall 252 can extend around adistal portion of receiver container 250. The needle 270 and sheath 280may extend through the wall 250. The stop 240 can be located on a distalportion of wall 252 and may comprise a soft material, for example a softelastomeric material such as silicone elastomer. The stop 240 may fitwithin a recess formed on the surface of wall 252, and the needle 270and the sheath 280 may extend through the soft elastomer stop 240, forexample. The sheath 280 may comprise the tapered portion 224 proximal tothe plurality of openings 236. The needle 270 can extend from tip 212through chamber 250 to the connector 290 (see FIG. 7A), for example. Thesheath 280 can extend from a first end 281 distal of the tapered portion224 to a second end 283. The second end 283 may comprise an opening 285into chamber 250. The outflow path of the displaced fluid from theimplantable device may extend through the plurality of openings 236 tochannel 239, along channel 239 to opening 285, and through opening 285and into receiver container 250.

FIG. 7C shows sheaths suitable for combination with the exchangeapparatus of FIGS. 7A and 7B. The sheath 280 can be configured in manyways (see 280A through 280K), and may comprise a wall thickness fromabout 0.0001 inches to about 0.01 inches, for example about 0.001 inches( 1/1000 inch, 25 μm). The sheath 280 may comprise an inside diametersized larger than the outside diameter of needle 270 so as to provide anannular channel extending axially between the needle and the sheath fromthe plurality of openings 236 to the opening 285. The diameter of eachof the holes can be within a range from about 0.0001 inches to about 0.1inches, for example within a range from about 0.001 inches to about 0.01inches.

The plurality of openings 236 may comprise one or more of many shapesand can be arranged in many ways. Each row may comprise from about 2 toabout 20 holes, for example, and may comprise circular, oval, ellipticalor other shapes, for example. The sheath 280 may comprise a sheath 280Ahaving four rows of circular holes. Each of the holes may have adiameter of no more than about one half of the thickness of the outsidediameter of the sheath 280, for example, and may be locatedcircumferentially at 90 degrees to each other, for example. Each of thefour rows may extend axially along the sheath 280. The rows can bespaced angularly at 90 degrees to each other, for example.

The sheath 280 may comprise sheath 280B having about two rows, each rowcomprising about four holes, each hole having a diameter of no more thanabout one eighth of the diameter of the outside diameter of the sheath280. The two rows may be spaced apart circumferentially at 180 degrees,and the holes may comprise holes cross-drilled through both sides of thesheath, such that each hole has a corresponding hole on the other row onan opposite side of the sheath.

The sheath 280 may comprise sheath 280C comprising about four crossdrilled holes, each hole having a diameter of no more than about threequarters of the diameter of the outside diameter of the sheath 280, forexample. The holes may comprise pairs of holes, in which the holes ofeach pair have corresponding axial locations. The holes can be arrangedin two rows spaced circumferentially at 180 degrees.

The sheath 280 may comprise sheath 280D comprising at least about threerows of at least about 3 holes, each hole having a diameter of no morethan about one quarter of the diameter of the outside diameter of thesheath 280. The rows can be spaced apart circumferentially at about 120degrees, for example.

The sheath 280 may comprise sheath 280E comprising at least about 40holes, each hole having a diameter of no more than about one tenth ofthe diameter of the outside diameter of the sheath 280.

The sheath 280 may comprise sheath 280F comprising slots. Each of theslots may comprise a narrow dimension across and a long dimensionacross. The long dimension can extend axially along the sheath 280 andmay extend a distance greater than the narrow dimension across. The longdimension can extend a distance greater than the outside diameter of thesheath 280 where the slots are located, for example. The narrowdimension across each slot may comprise no more than about half of theoutside diameter of the sheath, for example.

The sheath 280 may comprise sheath 280G comprising staggered rows ofholes. The plurality of openings 236 may comprise a first row and asecond row of cross drilled holes 236A, in which the holes of the firstrow are paired with the holes of the second row at a common axiallocation for each pair. A third row of holes and a fourth row of holesmay comprise cross drilled holes 236B located at 180 degrees to eachother and 90 degrees to the first row and the second row. The axiallocations of the third and fourth rows of holes can be staggered fromthe first and second rows of holes, such that the axial locations of theholes 236A of the first row and second row correspond to axial locationsaway from the holes 236B of the first row and the second row, forexample.

The sheath 280 may comprise sheath 280H comprising oval holes having along dimension and a short dimension, with the long dimension extendingtransverse to the axis of the sheath 280 and the short dimensionextending along the axis of the sheath 280. The oval holes can be spacedapart and located in rows extending along the axis of the sheath asdescribed herein, for example.

The sheath 280 may comprise sheath 280I comprising elongate oval holeshaving the long axis of the oval extending along the axis of the sheathand the narrow dimension of the oval extending transverse to the longaxis of the sheath, for example.

The sheath 280 may comprise sheath 280J comprising at least about threerows of at least about 3 oval holes, each oval hole having a maximumdimension across of no more than about one quarter of the diameter ofthe outside diameter of the sheath 280. The rows can be spaced apartcircumferentially at about 120 degrees as described herein, for example.

The sheath 280 may comprise sheath 280K comprising at least about 40holes, each hole having a diameter of no more than about one tenth ofthe diameter of the outside diameter of the sheath 280. The holes can belocated on opposite sides of the sheath 280, and may comprise crossdrilled holes, for example.

FIG. 7D shows one of the sheath openings 236 having a beveled channelsurface 284 to inhibit degradation of the penetrable barrier. Thethickness 286 of the sheath wall may be within a range from about 0.0001to about 0.01 inches, for example. The corner of 282 of the beveledchannel surface of the opening may comprise an angle to inhibitdegradation of the penetrable barrier, such as tearing with repeatedinjections.

FIG. 7E shows one of the sheath openings 236 having a rounded channelsurface of the opening and edge to inhibit degradation such as tearingof the penetrable barrier with repeated injections, in accordance withembodiments of the present disclosure;

FIG. 7F shows a schematic illustration of the parallel outflow pathsfrom the reservoir chamber 140. The first outflow path 140P1 extendsfrom the reservoir chamber 140 to the receiver container 250, and thesecond outflow path 140P2 extends from the reservoir chamber 140 acrossthe porous structure 150 to the vitreous humor 30 of the eye. As theintraocular pressure of the eye may be substantially less than thepressure of the implantable device during exchange, the intraocularpressure of the eye approximates atmospheric pressure. The secondoutflow path 140P2 extends comprises a pressure drop DP across theporous structure 150. The first outflow path 140P1 comprises thepressure drop DP across the plurality of openings 236, along the one ormore channels 239 extending from the plurality of openings to theopening 285, and through the one or more openings 285 into the receivercontainer 250. In many embodiments, the channel 254 and the opening 258each comprise air, such that the resistance to flow 254R of the channel254 and the resistance to flow 258R of the opening such that thepressure drop across channel 254 and the opening 258 can besubstantially less than the pressure drop DP, for example negligible.

In many embodiments, a valve 256V can be provided, so as to vary theresistance to flow of the outflow path to provide a bolus. The valve256V may comprise a porous structure 256, for example, or a stop,plunger or other mechanism so as to increase pressure and provide thebolus when the exchange apparatus 200 has received a predeterminedamount of displaced liquid from the reservoir container 140. The porousstructure 256 may comprise a gas such as air initially, and beconfigured to contact the liquid from the reservoir chamber when thepredetermined amount of fluid has been received and provide asubstantial increase in the resistance to flow 156R, such that the bolusis passed through porous structure 150. Examples of valves andmechanisms to provide the bolus injection are described in U.S. PCT Pat.App. No. PCT/US2011/046812, filed Aug. 5, 2011, entitled “InjectorApparatus and Method for Drug Delivery”, the entire disclosure of whichhas been previously incorporated herein by reference.

The pressure drops can be configured in many ways so as to inhibit abolus release into the eye when the therapeutic fluid is exchanged withthe implantable device fluid, or so as to release a bolus of therapeuticfluid through the porous structure of the implantable device, forexample. The therapeutic fluid 260 comprising therapeutic agent 110 isinjected through needle 270 into the reservoir chamber 140 of theimplantable device, so as to pressurize the implantable device chamberwith a force sufficient to pass a substantial portion of the implantabledevice fluid 262 into the receiver container 250. A pressure drop DPextends from the reservoir chamber of the implantable device through theplurality of openings 236, along channel 239 extending to opening 285,and through opening 285, such that the implantable device fluid 262 isreceived in receiver container 250. The outflow path from the reservoirchamber of the implantable device to the receiver container 250comprises a resistance to flow corresponding to a resistance to flow236R of the plurality of openings 236, the resistance to flow 239R ofthe channel 239, and the resistance to flow 285R of opening 285, forexample. The resistance 150R to flow of the porous structure correspondsto an amount of therapeutic fluid 260 passed from the reservoir chamberof the implantable device to the chamber of the eye containing vitreoushumor, for example. The amount of fluid into the receiver container suchas the chamber 250 relative to the amount of fluid through the porousstructure is related to the resistances based on parallel flow. Theamounts of flow to the receiver container 250 and through the porousstructure 150 correspond substantially to the following equations:(Amount through porous structure)/(Amount through receiver)=(Resistance236R+Resistance 239R)/(Resistance 150R)(Amount through porous structure)=(Amount through receiver)*(Resistance236R+Resistance 239R)/(Resistance 150R)(Amount to receiver container)=(Amount through porousstructure)*(Resistance 150R)/(Resistance 236R+Resistance 239R)

The resistance 150R corresponding to extended release of the therapeuticagent can be substantially greater than the resistance of the outflowpath to the receiver container 250 comprising resistance 236R andresistance 239R, such that the amount of bolus of therapeutic fluid 260and implantable device fluid 262 through the porous structure 150 can beless than about 1 μL combined, for example. Alternatively, theresistance to flow of the outflow path can be sufficient such that asubstantial amount of therapeutic agent 110 is released through porousstructure 150 with a bolus during exchange. The resistance to flow alongthe outflow path may comprise one or more of the resistance to flow 236Rof the plurality of openings 236, the resistance to flow 239R of thechannel 239 extending from the plurality of openings to the opening 285,or the resistance to flow 285R of the opening 285, for example, orcombinations thereof. The size and number of the plurality of openings236 and the thickness 286 of the sheath can determine substantially theresistance 236R of the plurality of openings. The length of the channel239 extending from the plurality of openings 236 to the opening 285, andthe transverse dimensions of the channel can determine substantially theresistance to flow 239R. For example the channel 239 may comprise aplurality of channels extending from the plurality of openings opening236 to the reservoir container 250.

The resistance to flow 150R can vary with the RRI of the porousstructure 150. In many embodiments, the resistance to flow 150R ofporous structure 150 is inversely related to the RRI of the porousstructure. For example, experimental testing with syringes and testtherapeutic devices has shown that a bolus can be achieved through aporous structure 150 having an RRI of about 0.06 when the resistance toflow of outflow path is sufficiently large and device 100 is constructedsuch that chamber 140 can be pressurized to at least about oneatmosphere, for example. However, porous structures having lower RRIscan provide a substantial resistance to flow so as to inhibit release ofa substantial bolus. For example a porous structure 150 having an RRI ofabout 0.02 has a resistance to flow 150R such that an attempt to pass asubstantial bolus amount through the porous structure 150 with aclinically acceptable injection time of 30 seconds or less may result insubstantial pressure, for example greater than about four atmospheres.

The resistance to flow 150R of the porous structure 150 comprising theplurality of straight channels 150SC varies with one or more of thecombined cross-sectional surface area of the channels 150SC, the numberof openings, the size of each of the openings, or the thickness 150T,and combinations thereof. The combined cross-sectional surface area ofthe channels 150SC may be no more than about 100,000 μm², so as toprovide a resistance to flow 150R of the porous structure 150 sufficientdecrease flow through the porous structure and provide exchange asdescribed herein. The combined cross-sectional surface area can bewithin a range from about 1000 μm² to about 100,000 μm², for example, soas to provide a resistance to flow 150R greater than the resistance toflow of the outflow path 140P1. For example, the combinedcross-sectional area within a range from about 1,000 μm² to about 30,000μm² may provide a substantial resistance to flow 150R, which may besubstantially greater than the resistance to flow of the outflow path.In many embodiments, the combined surface area is within a range fromabout 1,000 μm² to about 10,000 μm², and the resistance to flow 150R issubstantially greater than the resistance to flow of the outflow path soas to inhibit bolus release through the porous structure (see also FIGS.3A and 3B).

The resistance to flow of the outflow path comprising resistance 236Rand 239R may comprise about 5 percent of the resistance 150R to flow ofthe porous structure 150, such that about 5 μL of fluid flows throughthe porous structure and about 95 μL flows through the plurality ofopenings 236 and channel 239. The size and number of the plurality ofopenings and dimensions of channel 239 can be determined by a person ofordinary skill in the art based on the teachings described herein so asto provide a target amount of bolus for a target amount of injectedtherapeutic fluid.

As the therapeutic fluid 260 can be denser than the implantable devicefluid 262, a substantial portion of the fluid through the porousstructure 150 may comprise the therapeutic fluid 260, for example.

FIG. 8A shows a cross-sectional view of the apparatus to exchange fluidas in FIGS. 5 and 6 coupled to a syringe. The channel 239 extends fromthe plurality of openings 236 to a container 250 to receive the fluid ofthe implantable device. The distal portion 210 comprising tip 212 andopening 214 comprise a distal portion of needle 270. The channel 219extends along an axis 202 from the opening 214 to a connector 290. Theconnector 290 is configured to couple to a connector 320 of an injector.The injector may comprise a syringe 300 (not to scale). The injector maycomprise a container 310 comprising a therapeutic fluid for injection,and the container 310 can be fluidically coupled to the opening 214 ondistal tip 212 when the connector 320 engages the connector 290.

The sheath may comprise an annular configuration shaped for placementover the substantially annular needle, such that the sheath and needlecomprise a substantially concentric configuration extending along axis202.

The connector 290 of the exchange apparatus and the connector 320 of theinjector can be configured in many ways. For example, the connector 290and the connector 320 may comprise a standard connector such as a Luerconnector or a pressure fit connector. Alternatively, the connector 290may comprise a non-standard connector to limit access to the exchangeapparatus 200. For example the connector 290 may comprise a starconnector or other connector, and connector 290 may comprise a lock andkey mechanism. The lock and key mechanism may comprise a lock on theexchange apparatus configured to receive a key of the injector, suchthat the lock of connector 290 can receive the key of connector 320 tocouple the injector to the exchange apparatus and permit injection fromchamber 310 through opening 214. Alternatively, the syringe 300 may beaffixed to exchange apparatus 200, and syringe 300 provided with asingle dose of therapeutic agent.

The container 250 of the exchange apparatus may have a volume to limitand amount of fluid received from the implantable device and to limituse of the apparatus to a single use. For example, the volume of thecontainer may comprise no more than about 100 μL, for example no morethan about 50 μL, so as to limit and amount of fluid exchanged with theimplantable device and inhibit reuse of the exchange apparatus frompatient to patient. The implantable device can be provided to a healthcare provider with an amount of gas, such as air within the receivercontainer 250, and the receiver container may comprise a structure alonga vent path to limit the amount of fluid that can be received by thecontainer 250.

The exchange apparatus 200 may comprise a porous structure 256 toinhibit passage of the fluid of the implantable device and limit theamount of fluid exchanged. The porous structure 256 may comprise amaterial to pass a gas, such as air and inhibit flow of a liquid, suchas the fluid of the implantable device. The material may comprise one ormore of a fabric, a porous fabric, a semipermeable membrane, an airpermeable material, a moisture vapor transfer waterproof fabric, ahydrophilic porous material, or a porous sintered material, for example.The channels extending through the porous structure 256 may comprise agas, such as air and a lower resistance to flow of the gas and asubstantially greater resistance to flow of a liquid, such as thetherapeutic fluid, such that the exchange is substantially inhibitedwhen receiver container 250 is substantially filled with fluid ofimplanted device and the fluid exchanged with the implanted devicecontacts the porous structure 256. The porous structure 256 may compriseone or more of a fabric, a porous fabric, a semipermeable membrane, anair permeable material, a moisture vapor transfer waterproof fabric, ahydrophilic porous material, or a porous material or a porous sinteredmaterial, for example.

The exchange apparatus may comprise a structure 259 composed of amaterial penetrable with a needle to draw a sample from the receivercontainer. The structure 259 may comprise one or more materials suitablefor penetration with a needle such as one or more of rubber or siliconeelastomer, for example. The structure 259 may comprise the porousstructure 256, for example, and the material penetrable with the needlemay comprise one or more of a fabric, a porous fabric, a semipermeablemembrane, an air permeable material, a moisture vapor transferwaterproof fabric, a hydrophilic porous material, or a porous materialor a porous sintered material, for example.

FIG. 8B shows an embodiment of an implantable therapeutic device 100comprising a lock and key mechanism 850 to place a therapeutic agent inthe implantable device. The lock and key mechanism 350 comprises a lock360 and a key 370. The lock 360 can be located on the implantable deviceto inhibit access to the reservoir chamber of the implantable device.The exchange apparatus 200 comprises the key 370 to access the reservoirchamber to place the therapeutic agent 110 as described herein. The lockcan be configured in many ways and may comprise one or more of adeflected channel, a curved channel, a helical channel, a serpentinechannel, engagement structures, a magnet, a door, a movable door, atumbler, a cylinder, pins or a shear line, for example. The key can beconfigured in many ways so as to correspond to the lock and may compriseone or more of a deflectable elongate structure, a curved elongatestructure, a helical elongate structure, a serpentine elongatestructure, engagement structures sized to engage engagement structuresof the lock, for example.

In many embodiments, the lock 360 inhibits access with a straight rigidneedle, so as to inhibit placement of the therapeutic agent which may beineffective or inappropriate when placed in the therapeutic device. Forexample, the exchange apparatus 200 can be delivered to the physicianwith a predetermined therapeutic agent formulation and key, and theimplantable device has the lock configured to receive the key to placethe therapeutic agent, such that access to the implantable device can belimited substantially.

In many embodiments, the lock 360 comprises the deflected channel 364,which may comprise one or more of a bent channel, a curved channel, ahelical channel, or a serpentine channel, for example. The lock 360 maycomprise a stiff substantially non-penetrable biocompatible material,for example one or more of rigid plastic, polymethylmethacrylate(hereinafter “PMMA”), polycarbonate, metal, or titanium, for example.The key 370 may comprise one or more of many components and structuresof elongate structure 201 as described herein. The key 370 may compriseone or more of a deflectable key or a deflected key configured to extendalong the deflected channel 364 to deliver the therapeutic fluid 260 andreceive the implantable device fluid 262. The lock comprises anengagement structure 362 to engage an engagement structure 372 of thekey. The engagement structure 362 may comprise an inner surface of thechannel 364, and the outer surface of the deflectable key engages theinner surface of the channel so as to deflect the elongate structure 201to advance along channel 364.

FIG. 8B1 shows an embodiment of a deflectable elongate structure 201 inan unloaded configuration prior to insertion in the lock 360 of FIG. 8B.The elongate structure comprises an axis 202, and the elongate structuremay extend substantially along the axis 202 so as to provide columnstrength to the elongate structure 201 to penetrate the penetrablebarrier 184 of access port 180. The elongate structure 201 may comprisea resistance to deflection sufficiently low so as to advance alongchannel 364 and a column strength sufficient to penetrate tissue and thepenetrable barrier. The deflectable elongate structure 201 can bedeflected substantially away from axis 202 when advanced into the lock360.

The lock 360 may comprise a rigidity sufficient to inhibit penetrationwith a straight needle, and the channel 364 can be extend internallywith lock 360.

The key 370 comprising the elongate structure 201 can extend throughtissue such as the conjunctiva and epithelium to reach the lock 360, andthe key can be configured to penetrate the tissue. The penetration ofthe tissue and penetrable barrier 184 inhibits contamination of thereservoir chamber as the barrier function of the conjunctiva 16 andTenon's capsule 17 can be substantially maintained. The deflectableelongate structure 201 can be made of one or more of many components andmay comprise sheath 280 and needle 270. The needle and sheath can beconfigured to deflect together when advanced along channel 364. Thedeflectable needle may comprise a metal, for example Nitinol, and thesheath may comprise a polymer such as polyimide, for example.

FIG. 8B2 shows an embodiment of a deflected elongate structure 201 in anunloaded configuration prior to insertion in the lock of FIG. 8B. Thekey 370 comprising deflected elongate structure may comprise one or moreof many materials providing a stiffness sufficient to retain thedeflected shape in the unloaded configuration. In the unloadedconfiguration, the deflected elongate structure 201 of key 370 extendsaway from axis 202. The deflected elongate structure 201 may comprise apreformed deflection profile corresponding to the path of channel 364extending through the lock 360 from a first side of the lock toward theconjunctiva to a second side of the lock toward the reservoir chamber140.

FIG. 8C1 shows an embodiment of an implantable therapeutic device 100comprising a lock 360 and an exchange apparatus 200 comprising arotatable key 370 to the lock 360. The exchange apparatus 200 can beadvanced toward the implantable device 100 and rotated as shown witharrows 374. The engagement structures 372 of the key couple to theengagement structures 362 of the lock, such that the lock 360 opens toallow access of the elongate structure 201. The engagement structuresmay comprise one or more of many structures, for example magnets, teeth,or notches, and the engagement structures can be spaced apart atappropriate distances such that the engagement structures of the lockare keyed to the engagement structures of the key to allow access. Forexample the engagement structures 372 of the key may comprise magnets,and the engagement structure of the lock may comprise a magneticmaterial such that the key can be opened with the lock and the magneticfield extending through the conjunctiva 16 and the Tenon's capsule 17,for example. Alternatively, the conjunctiva and/or Tenon's capsule canbe displaced and the engagement structures 372 of the key can contactthe engagement structures 362 of the lock to allow access to thereservoir chamber.

FIG. 8C2 shows an embodiment of the implantable therapeutic device 100of FIG. 8C1 in a unlocked configuration in which the elongate structure201 extends through the open lock and penetrable barrier 184 to accessthe reservoir chamber 140 of the implantable device 100. The exchangeapparatus can place the therapeutic fluid 260 in the implantable device100 and receive the implantable device fluid 262 in the receivercontainer 250 as described herein.

FIG. 8D1 shows an embodiment of an implantable therapeutic devicecomprising 100 a slide lock 360 and exchange apparatus 200 comprising aslidable key to engage the slide lock. The exchange apparatus 200 can beadvanced toward the implantable device 100 and slid as shown with arrows374. The engagement structures 372 of the key couple to the engagementstructures 362 of the lock, such that the lock 360 opens to allow accessof the elongate structure 201. The engagement structures of the slidelock 360 and slide key 370 may comprise structures similar to therotatable key and lock described with reference to FIG. 8C1.

FIG. 8D2 shows an embodiment of an implantable therapeutic device 100 inan unlocked configuration in which the elongate structure 201 extendsthrough the open lock 360 and penetrable barrier 184 to access thereservoir chamber 140 of the implantable device. The exchange apparatuscan place the therapeutic fluid 260 in the implantable device 100 andreceive the implantable device fluid 262 in the receiver container 250as described herein.

FIG. 8E shows an embodiment of an implantable therapeutic device 100comprising a lock 360 and the elongate structure 201 of the exchangeapparatus 200 comprising the key 370. The elongate structure 201 can beconfigured in many ways so as to comprise the key 370. The engagementstructures 372 of the key 370 can be located near a distal end 212 ofthe elongate structure 201, for example. The engagement structures 272can be affixed to the needle 270 and may comprise annular structuresextending around the needle. Alternatively or in combination, the sheath280 of the elongate structure may comprise the engagement structures.For example, the one or more openings 289 of the sheath 280 can be sizedand located so as to comprise the engagement structures 372 of the key370.

The lock can be configured in many ways to receive the key, and theengagement structures 362 of the lock may comprise pins aligned to ashear plane 368 when the key is inserted, for example.

FIG. 9 shows a container 400 to receive and store the exchange apparatus200. The container 400 may comprise a barrier material 410 to inhibitevaporation from within the container to the outside environment, a cap430 and a base supporting a soft penetrable material 420. The cap 430may comprise a protrusion such as an annular protrusion 432 to sealaround an outer portion of the wall of the container. The cap 430 maycomprise a retention structure to hold the injector apparatus, forexample a second protrusion, such as an annular protrusion 434 toreceive and hold the exchange apparatus 200. The cap 430 may comprise asoft barrier material, such as an elastomer, for example.

FIG. 10 shows an exchange apparatus 200 having the implantable devicefluid 262 comprising a fluid sample 264 within the receiver container250. The receiver container 250 can be coupled to the elongate structure201. The channel 254 can extend from the container to 250 to opening258. The receiver container 250 may comprise a combination of one ormore of the therapeutic fluid 260, the implantable device fluid 262comprising sample fluid 264. Depending on the exchange apparatus andorientation, the implantable device fluid 262 comprising sample fluid264 may comprise a substantial majority of the fluid of the receivercontainer 250.

FIG. 11 shows the exchange apparatus 200 having the fluid sample 264placed partially within the storage container 400. The cap 430 is shownover but not yet covering the vent channel 254 extending from thereceiver container 250 to the opening 258.

FIG. 12 shows a cap 430 of the storage container placed over the outletchannel opening 258 of channel 254 coupled to the receiver container 250of the exchange apparatus, so as to inhibit one or more of leakage orevaporation from container 250.

FIG. 13 shows an elongate structure 201 of the exchange apparatus placedwithin a soft penetrable material 420 near the bottom of the storagecontainer and the cap placed over the container so as to seal theexchange apparatus container. The soft penetrable material 420 maycomprise a soft material capable of sealing, for example a softelastomeric material such as silicone elastomer.

FIG. 14 shows an apparatus 500 to remove the sample fluid from thereceiver container 250 of the exchange apparatus 200. The apparatus 500comprises a sample container 400, a plug 520, a syringe 540 topressurize the receiver container 250, and a coupling 530 to couple thesyringe to the receiver container of the exchange apparatus 200. Thecoupling 530 may comprise a receptacle 536 to receive the proximal endportion of the exchange apparatus 200. The receptacle 536 may comprise astructure 532 to couple the syringe to the coupling, for example a Luerconnector, a Luer-Lok™ connector, or other known connector, for example.The retention structure 532 to retain the exchange apparatus 200 and acontact structure 534 to contact the outer wall of the exchangeapparatus and fluidly couple the syringe to the opening 528 when theexchange apparatus 200 is retained with the coupling 530. The contactstructure 534 may inhibit flow of injection fluid from syringe 540, suchas air, between the retention structure 532 and wall 252 of the exchangeapparatus, for example with a seal between the retention structure 532and the wall 252 of the exchange apparatus 200.

FIG. 15 shows a cap 520 placed on the connector 290 to couple thesyringe to the exchange apparatus, so as to inhibit fluidic flow fromsyringe 540 through the needle of the elongate structure 201.

FIG. 16 shows the exchange apparatus placed within receptacle 536 of thecoupling 530 so as to couple the receiver container 250 with the syringe540. The syringe 540 can pressurize the channel 254 so as to displacethe implantable device fluid comprising the sample fluid 264 from thereceiver container 250 into a sample container 400 for analysis. Theannular protrusion 534 can engage the outer wall 252 of the exchangeapparatus 200 form a seal and pressurize chamber 250 when the plunger ofsyringe 540 is depressed. The pressurization of chamber 250 urges theimplantable device fluid 262

FIG. 17 shows an exchange apparatus 200 coupled to a removable receivercontainer 250. The removable container 250 may comprise a penetrablebarrier, for example a septum. The exchange apparatus 200 can be coupledto a syringe 300. The exchange apparatus can be coupled to a device 100implanted in an eye with the elongate structure 201 configured to extendthrough the conjunctiva 16 and the penetrable barrier 184. The exchangeapparatus may comprise a first channel coupled to the plurality ofopenings to receive the fluid from the implantable device, and a secondchannel coupled to a vent. The first channel 239 may extend to a firstneedle 710 to puncture container 250 and the second channel may extendto a second needle 720 to puncture the container 250. The first needlemay have a first opening 712, and the second needle may have a secondopening 722. The first opening can be located below the second opening,such that the second opening allows air to pass when liquid passesthrough the first opening.

FIG. 18 shows the exchange apparatus 200 coupled to the implanted device100 so as to exchange fluid and receive sample fluid 264 from theimplanted device. The container 250 can be coupled to the exchangeapparatus during exchange.

FIG. 19 shows the exchange apparatus removed from the implanted deviceand the receiver container 250 detached from the exchange apparatus. Thesample fluid 264 from the implantable device can be contained within thecontainer 250.

FIG. 20A shows components of a container 400 to remove a sample fluid264 from exchange apparatus 200. The container 400 may comprise asealable container having a wall composed of a barrier material 410 toinhibit evaporation, a cap 430 and an annular protrusion 432. A support450 can be placed within container to receive and hold the exchangeapparatus 200 within the container. The support 450 may comprise a pieceof soft elastomeric tubing such as silicone tubing, for example.

FIG. 20B shows an exchange apparatus 200 placed in the container 400having components as in FIG. 20A. The exchange apparatus is placed suchthat the wall 252 of container 250 rests on the support 450. Theelongate structure 201 extends below the support 450. The container 400comprises an axis 400A, which axis may be aligned with the axis ofexchange apparatus 200. The opening 258 coupled to container 250 withchannel 254 is exposed to air.

FIGS. 20C and 20D show removal of implantable device fluid 262comprising sample fluid 264 from exchange apparatus. The sample fluid264 may be drawn into the container 400 with aspiration. A syringe 300can be coupled to the exchange apparatus 200 with a connector 320 suchas a locking connector, for example. The syringe 300 may comprise apiston 302 connected to a plunger 304 which allows the piston to beadvanced and pulled back. The syringe 300 comprises a chamber 310 havinga volume defined with the location of piston 302.

The piston of the syringe can be drawn outward to draw air from chamber440, which chamber draws sample fluid 264 into chamber 440.

FIG. 21 shows a method 1800 of removal from an exchange apparatus with aremoval container as in FIGS. 20A to 20D. A step 1810 removes theexchange apparatus 200 from the syringe after injection of thetherapeutic fluid. The implantable device fluid comprising the samplefluid is contained in the receiver container 250.

A step 1810 removes therapeutic fluid 260 from the needle of theelongate structure 201 with injection of a gas comprising air from asyringe 300.

A step 1820 depresses the plunger towards the needle.

A step 1830 places the exchange apparatus 200 on the support 450 ofcontainer 400 with the exchange apparatus coupled to syringe 300. Thesupport 450 coupled to exchange apparatus 200 may define a chamber 440.The support 450 can be shaped to inhibit air flow between and outersurface of the exchange apparatus and an inner surface of the support450, for example with a seal formed between the outer surface of theexchange apparatus 200 and the inner surface of the support 450. Thesupport may comprise a soft material, such as a soft elastomericmaterial, for example.

A step 1840 draws air from chamber 440 with syringe 300 through theinjection needle of the elongate structure extending into chamber 440.The implantable device fluid 262 comprising sample fluid 264 isdisplaced from the receiver container with air drawn into the receivercontainer 250 through opening 258 of channel 254. The implantable devicefluid 262 comprising sample fluid 264 falls to the lower end of chamber440 and is contained on an inner surface of container 400.

A step 1850 removes the exchange apparatus 200 and syringe 300 from thesample container 400. The cap 430 is placed on the container 400, so asto inhibit evaporation of the implantable device fluid 260 comprisingsample fluid 264.

FIG. 22 shows an exchange apparatus 200 having a receiver container 250comprising a penetrable barrier structure 259 on a side port to remove asample from the receiver container with a needle and syringe. Thesyringe can draw implantable device fluid 262 comprising sample fluid264 from the receiver container 250 through a needle 330 passing throughthe penetrable barrier structure 259 on the side port.

FIG. 23A shows an exchange apparatus 200 having a receiver container 250coupled to a sample container 400 and a syringe 300 to displace fluidfrom the receiver container 250. The sample container 400 is placed overthe plurality of openings 236 and a needle 330 of a syringe 300 extendsinto a chamber 440 the sample container. The syringe 300 can draw fluidfrom chamber 440 so as to displace fluid from the receiver container250. The channel 254 extends from container 250 to opening 258. Fluiddrawn through needle 330 into syringe 300 urges the implantable devicefluid 262 comprising sample fluid 264 through the one or more openingscomprising the plurality of openings 236, and air can move inwardthrough opening 258 and along channel 254 to displace the implantabledevice fluid 262 comprising sample fluid 264. The needle 270 extendsthrough the sample container 400 such that the distal end of the needleextends beyond sample container 400. The plurality of openings 236 maycomprise a plurality of openings of sheath 280.

FIG. 23B shows the sample container 400 of FIG. 23A placed over theplurality of openings 236 of the exchange apparatus. The samplecontainer 400 may comprise a first penetrable barrier comprisingpenetrable barrier material 420 and a second penetrable barriercomprising penetrable barrier material 420. A first septum 422 can belocated opposite a second septum 422, for example. The elongatestructure 201 can extend through the first penetrable barrier and thesecond penetrable barrier so as to position the one or more openingsbetween the first penetrable barrier and the second penetrable barrier.The sample container 400 may comprise a wall composed of a barriermaterial 410, and the wall may comprise an amount of rigidity sufficientto resist deflection when the sample is drawing with needle 330. Thewall may comprise an annular shape, for example a tubular geometry. Theneedle 270 may extend through the second penetrable barrier so as toinhibit fluidic coupling of the syringe 300 and needle 330 with theopening on the distal end of needle 270. The sample container 400 can beshaped in many ways, for example with a spherical ball or other shapehaving a walls composed of penetrable barrier material 410 such that theneedle tip can extend through both side of the container 400.

FIGS. 24A and 24B show an exchange apparatus having a receiver container250 coupled to a syringe 300 with a sample container 400 placed overopenings 236 of the exchange apparatus 200 so as to remove a samplefluid 264 from the receiver container 250. The sample container 400comprises a chamber 440 enclosed with a wall comprising a barriermaterial 410 and a penetrable barrier material 420, in which thepenetrable barrier material may comprise a septum, for example. The wallof the container 400 may comprise one or more of many shapes such asannular, spherical, cubic, ellipsoidal or oval, for example. Theelongate structure 201 comprising needle 270 and sheath 280 can beadvanced into the container 400 so as to place at least one opening ofthe plurality of openings 236 within the chamber 440 and the distalneedle tip comprising the opening to place therapeutic fluid within thechamber 440. The needle can be coupled to syringe 300, and fluid drawnfrom chamber 440 with syringe 300 through an opening in the distal tipof needle 270. The fluid drawn through the needle 270 is replaced withthe fluid passed through the plurality of openings 236.

The receiver container 250 comprising the implantable device fluid 262comprising sample fluid 264 is fluidically coupled to the plurality ofopenings as described herein such that the implantable device fluid 262comprising the therapeutic fluid 264 is passed through the plurality ofopenings. The channel 254 extends from the receiver container 250 to theopening 258 such that air may be drawn into the receiver container 250to replace the volume of the displaced implantable device fluid 262comprising sample fluid 264. In many embodiments, the implantable devicefluid 262 comprising the sample fluid 264 comprises a liquid comprisingwater as described herein.

FIG. 25A shows an exchange apparatus 200 comprising a removable receivercontainer 250 comprising a removable sheath 280 placed over a needle270. The receiver container 250 may comprise the sample container 400.The wall 252 of container 250 and needle 270 can be configured forremoval and separation from the needle 270 so as to provide the samplecontainer 400. The sheath 280 may be supported on a distal end of thewall 252 of container 250, such that the sheath 280 can be supportedwith the wall 252 of container 400 when removed. A plug 960 comprisingpenetrable barrier material 420 can be placed over the sheath 280 needle270 prior to removal of the needle to inhibit leakage of the implantabledevice fluid 262 comprising sample fluid 264.

FIG. 25B shows the removable container 400 of FIG. 25A with a plug 960comprising penetrable barrier material 420 placed over the sheath 280and the needle 270 removed, such that the sheath 280 is supported withthe container 400. The implantable device fluid 262 comprising samplefluid 264 remain in the receiver container 250 comprising samplecontainer 400 subsequent to removal of the needle 200.

FIG. 25C shows the removable container of FIGS. 25A and 25B with plug960 placed over the sheath 280 and a cap 430 over the removable receivercontainer. The cap 430 can inhibit one or more of evaporation or leakageof the implantable device fluid 262 comprising sample fluid 264.

FIGS. 26A to 26E show a centrifuge used to remove the fluid sample fromthe receiver container of the exchange apparatus.

FIG. 26A shows the exchange apparatus 200 comprising the receivercontainer 250 having the implantable device fluid 262 comprising thesample fluid 264 contained therein, in which the exchange apparatus isconfigured for placement within the sample container 400. The samplecontainer 400 may comprise a centrifuge tube having a support 450 asdescribed herein. The exchange apparatus 200 may comprise a channel 254extending from receiver container 450 to opening 258, so as to couplethe opening 258 to the plurality of openings 236. As the implantabledevice fluid 262 comprising sample fluid 264 contained within receivercontainer 250 comprises a density greater than air, the fluid within thereceiver container can be displaced through the plurality of openings236 of the exchange apparatus 200. Air can pass through opening 258 andchannel 254 into the receiver container 250 to replace the volume ofimplantable device fluid 262 comprising sample fluid 264 displaced fromreceiver container 250 and through the plurality of openings 236.

FIG. 26B shows the exchange apparatus 200 placed in the sample container400.

FIG. 26C shows the exchange apparatus 200 in the sample container 400configured for placement in a centrifuge 500.

FIG. 26D shows the exchange apparatus 200 in the sample container 400placed in a centrifuge 500.

FIG. 26E shows the exchange apparatus 200 within the sample container400 subjected to force within the centrifuge 500, such that the force ofthe centrifuge 500 is sufficient to displace the implantable devicefluid 262 comprising sample fluid 264 from the receiver container 400through the plurality of openings 236 as described herein. Theimplantable device fluid 262 comprising sample fluid 264 is deposited onthe lower end portion of an inner surface the sample container 400.

FIG. 26F shows an embodiment comprising exchange apparatus 200 placed ina sample container 400 comprising a centrifuge tube. The container 400may comprise a barrier material 410 to inhibit evaporation from withinthe container to the outside environment, a cap 430 and a basesupporting a soft penetrable material as described herein. The cap 430may comprise a protrusion such as an annular protrusion 432 to sealaround an outer portion of the wall of the container, for example. Whenthe cap 430 is placed on the top of the tube, the chamber 440 can besealed so as to inhibit evaporation, for example. The barrier 410 maycomprise sufficient strength so as to inhibit penetration with theneedle of the elongate structure 201 when placed in a centrifuge, forexample.

FIG. 26G shows an embodiment comprising an exchange apparatus 200 placedin a sample container 400 comprising a centrifuge tube, in which thecentrifuge tube comprises a support 450 comprising an annular shoulder450S of the tube to engage and hold the exchange apparatus. The support450 can engage the exchange apparatus 200 to support the exchangeapparatus in a centrifuge, for example, with a gap extending between thelower surface of the tube and the distal tip of the needle of theexchange apparatus so as to inhibit penetration of the sample containerwith the needle. The container 400 may comprise additional structures asdescribed herein.

FIG. 26H shows an embodiment of an exchange apparatus 200 placed in asample container 400 comprising a centrifuge tube, in which thecentrifuge tube comprises a support 450 comprising restricted portion tohold the exchange apparatus. The support 450 may comprise a rib toengage the exchange apparatus 400, for example. The rib 450R can beformed with a recess in the outer surface of the container 400. Thesupport comprising the rib can engage and support the exchange apparatussuch that a gap extends between the distal end of elongate structure 201and the lower surface of the tube

FIG. 27A shows an embodiment of a collapsible fluid separator 510 foruse with a therapeutic device. The collapsible fluid separator 510 maycomprise a plunger and can be penetrable with a needle and configured toform a seal around the outer perimeter. The fluid separator 510 maycomprise a distal shape profile corresponding to the distal portion ofthe reservoir chamber so as to displace fluid from the distal portionnear the porous structure 150 as described herein. The fluid separator510 may be penetrated with a needle and may comprise a septum, forexample. The penetrable fluid separator can be penetrated with a needlefor fluid removal and refill. In many embodiments, the fluid separator510 is configured to expand and contract so as to contact the inner wallof the reservoir chamber 140 and form a seal with wall of the reservoirchamber. The fluid separator 510 can be configured to expand andcontract to maintain contact with a wall having a varyingcross-sectional dimension such as a varying diameter. In manyembodiments, the fluid separator 510 is configured to contract so as todecrease the volume of the fluid separator such that the volume of thereservoir chamber available to receiver therapeutic fluid 260 can besubstantially maintained.

FIG. 27B shows an embodiment of plunging structure 520 comprising anexchange needle 522 and an engagement structure comprising shoulder 524suitable for use with the collapsible fluid separator as in FIG. 27A anda therapeutic device. The needle 522 comprises an internal channel toreceiver fluid to remove the implantable device fluid and place thetherapeutic fluid in the reservoir chamber. The plunging structure maycomprise an engagement structure, for example shoulder 524, so as toengage the collapsible separator and advance the fluid separator 510distally toward the porous structure with a thrusting movement.

FIG. 27C shows an embodiment of the collapsible fluid separator as inFIG. 27B placed within a reservoir chamber 140 of a therapeutic device100. The collapsible separator 510 is shown near the proximal end of theimplantable therapeutic device 100, which comprises the access port 180and retention structure 120. The access port 180 may comprise apenetrable barrier 184 capable of penetration with the needle of theplunging structure, or a removable structure such as a cap, plug or thelike which can be removed to introduce the plunging structure.

FIG. 27D shows an embodiment of the plunger 520 comprising the exchangeneedle and shoulder as in FIG. 27B advanced into the access port 180 ofthe therapeutic device having the collapsible fluid separator 510 placedwithin the reservoir chamber 140 of the therapeutic device as in FIG.27C.

FIG. 27E shows an embodiment of the plunging structure 520 andcollapsible fluid separator 510 advanced within the reservoir chamber140 of the therapeutic device as in FIG. 27D so as to displace theimplantable device fluid 562 from the reservoir chamber through theneedle. The collapsible fluid separator 510 has expanded from a firstcross-sectional dimension across, for example a first diameter, to asecond cross-sectional dimension across, for example a secondcross-sectional diameter larger than the first. The expandable andcollapsible fluid separator 510 can expand or collapse so as to contactthe side wall of the reservoir chamber 140 and inhibit flow between alower side and an upper side of the expandable and collapsible fluidseparator 510. The inhibited flow around the outer perimeter of thefluid separator can provide pressurization of the implantable devicefluid near the tip of exchange needle 522 so as to drive implantabledevice fluid into the exchange needle. Alternatively or in combination,suction can be applied to the exchange needle so as to draw implantablefluid from the exchange needle 522 and advance the separator 510 towardthe porous structure 150. In many embodiments, the porous structure 150comprises a resistance to flow sufficient to inhibit flow of one or moreof the implantable device fluid or the therapeutic fluid through theporous structure during the exchange as described herein.

FIG. 27F shows an embodiment of the collapsible fluid separator 510advanced within the reservoir chamber to a location near the distal endof the reservoir chamber so as to displace most of the implantabledevice fluid from the reservoir chamber through the needle 522. Theneedle 522 may contact porous structure 150, which may comprise a rigidporous structure as described herein.

FIG. 27G shows an embodiment of the collapsible fluid separator 510moved from the distal end of the reservoir chamber comprising porousstructure 150. The collapsible fluid separator 510 can be moved in oneor more of many ways to place the therapeutic fluid in the distalportion of the reservoir container. The therapeutic fluid can beinjected through the needle 522, or another needle for example, so as toplace the therapeutic fluid 260 in the distal portion of the container.Alternatively or in combination, the expandable and collapsible fluidseparator can be pulled toward the proximal end of the reservoir chamberso as to draw therapeutic device fluid through the needle and into thereservoir chamber from an external container of the exchange apparatusas described herein.

FIG. 27H shows an embodiment of the collapsible fluid separator 510moved from the distal end of the reservoir chamber to the proximal endof the reservoir chamber so as to fill substantially the reservoirchamber with therapeutic fluid 260. The collapsible fluid separator 510comprises a substantially decreased size and volume so as to fitsubstantially within the neck of the reservoir chamber such that asubstantial amount of the volume of the reservoir is filled withtherapeutic fluid 260.

FIG. 27I shows an embodiment of a substantially non-collapsible fluidseparator 510 placed within the reservoir chamber 140 of therapeuticdevice 100 having a substantially fixed cross sectional size. Thecontainer 130 comprising reservoir chamber 140 may comprise asubstantially cylindrical tubular barrier 160. The fluid separator maycomprise a piston slidable within the tubular barrier 160, for example.

FIG. 28A shows an embodiment of an exchange apparatus 550 comprising aballoon 560 supported on a elongate tubular member 580 capable ofintroduction into an implantable therapeutic device 100 as to exchangethe implantable device fluid 262 with a therapeutic fluid 260.

The exchange apparatus 550 may comprise an elongate tubular structure570 shaped to penetrate tissue, for example a needle. The elongatetubular structure 570 shaped to penetrate tissue can be advanced intoaccess port 180 through penetrable barrier 184, followed by balloon 560and the distal end of elongate tubular member 580, such that balloon 560is placed in the reservoir chamber.

The balloon 560 may comprise a highly compliant balloon. As the balloon560 is inflated, implantable device fluid is displaced out of thereservoir chamber. The balloon 560 may comprise Pebax™ or another highlyelastic material such as silicone, for example, or a non-elasticmaterial capable of being one or more of folded, rolled or compressed,for example. The balloon 560 may comprise a tubular structure andsupported on the outside diameter of the needle or a sheath over theneedle prior to inflation. The balloon may be designed to inflateproximally to distally, e.g. top down, to contact the inner wall of thereservoir chamber and displace fluid toward the vent needle opening. Theballoon may be inflated with therapeutic fluid 260. The balloon may beretractable within a sheath, for example. A sheath may be provided todeliver the balloon through the penetrable barrier, for example with thesheath penetrating the penetrable barrier to protect and place theballoon in the reservoir chamber without substantial contact of theballoon to the penetrable barrier when the balloon is placed.

The exchange apparatus 550 comprises components and structure to inflateballoon 560 and remove implantable device fluid 262 from the reservoirchamber 140. The elongate tubular structure 570 shaped to penetratetissue may comprise a channel 572 to fluidically couple the reservoirchamber 140 with an external container, for example. The elongatetubular member 580 may comprise a first lumen 582 and a second lumen584, for example. The elongate tubular member 580 can be connected toone or more containers, syringes, or pumps, for example. The elongatetubular member 580 may comprise a first connector 588 fluidciallycoupled to first lumen 582, and a second connector 586 fluidciallycoupled to the second lumen 584, for example. The first lumen 582 of theelongate tubular member 580 can fluidically couple to channel 572 andexternal connector 588, for example, such that the implantable devicefluid 262 can be received in a receiver container as described herein.The second lumen 584 can fluidically couple the connector 586 to balloon560, so as to allow inflation of the balloon, for example with asyringe. The connector 586 and the connector 588 may each comprisestandard known connectors as described herein, for example. The exchangeapparatus 550 may comprise one or more catheter components known to aperson of ordinary skill in the art in the field of catheter design andsuitable for combination in accordance with the teachings describedherein, for example.

FIG. 28B shows an embodiment of the balloon 260 as in FIG. 28A inflatedwithin the therapeutic device to displace the implantable device fluid262. The balloon 560 may be inflated with the therapeutic fluid 260 asdescribed herein, for example. The therapeutic fluid 260, or anotherfluid, can be injected into the balloon with a syringe coupled toconnector 586 such that the injected fluid travels along lumen 584 toinflate the balloon 560. The implantable device fluid 262 can bedisplaced with the balloon so as to urge the implantable device fluid262 into channel 572 of the elongate structure 260 shaped to penetratetissue. The porous structure 150 may comprise a substantial resistanceto flow to inhibit flow of implantable device fluid 262 through theporous structure.

FIG. 28C shows an embodiment of the balloon 560 deflated within thetherapeutic device 100 to provide space for the therapeutic fluid 260.In many embodiments, the receiver container as described herein, forexample a bag, can be disconnected from connector 588, and a syringecomprising therapeutic fluid 560 coupled to connector 580. The syringeor other fluid source used to fill balloon 560 can be decoupled fromlumen 582, and the therapeutic fluid 560 can be injected into elongatestructure 570 to place therapeutic fluid 260 in reservoir chamber 140such that the fluid within balloon 560 is displaced and the size ofballoon 560 decreased. When the size of balloon 560 has decreasedsufficiently, the balloon 560 and elongate structure 570 can be removedfrom the implantable device 100 by passing through the penetrablebarrier 184. The balloon 560 and elongate structure 570 can be removedin many ways, for example by one or more of pulling on elongate tubularmember 580 or injecting therapeutic fluid 560 into reservoir chamber140, so as to displace balloon 560 and elongate structure 570 from thereservoir chamber 140. In many embodiments, reservoir chamber 140 can bepressurized with injection of therapeutic fluid 260 so as to displacethe balloon 560 and elongate structure 570 through the penetrablebarrier 184 with pressure.

FIG. 28D shows an embodiment of the balloon 560 punctured within thetherapeutic device 100 so as to release the therapeutic fluid 260 fromthe balloon to the reservoir chamber 140 of the therapeutic device 100.The therapeutic 100 may comprise internal structures 590 to puncture theballoon and release the therapeutic agent. The internal structure 290may comprise a sharp tip, for example a needle tip to penetrate theballoon 560 and release the therapeutic agent. The internal structure590 can be supported on the wall of the reservoir chamber, for example.

FIG. 29A shows an embodiment of a deflectable fluid separator 600 placedwithin an implantable therapeutic device 100. The deflectable fluidseparator 600 inhibits mixing of the implantable device fluid 262 withthe therapeutic fluid 260. The deflectable fluid separator 600 canseparate portions of the reservoir chamber so as to define a firstportion 141 on a first side of the chamber and a second portion 143 on asecond side of the reservoir chamber. The first portion 141 of thereservoir chamber 140 may be coupled to a first porous structure 151 toprovide sustained release from the first portion and the second portion143 of the reservoir chamber 140 may be coupled to a second porousstructure 153 to provide sustained release from the second portion. Theporous structures can be substantially similar to porous structure 150as described herein. The deflectable fluid separator 600 may comprise abarrier material to inhibit flow of the therapeutic agent, and maycomprise one or more of a bladder, diaphragm, a membrane, or a sheet ofdistensible material, for example. The deflectable fluid separator maycomprise an expandable bladder capable of deflection to either side ofthe reservoir chamber, for example. The deflectable fluid separator maybe used with exchange apparatus 200 as described herein. The elongatestructure 201 of the exchange apparatus may comprise a bi-needle designas described herein, for example with a first needle to advance fluidinto a first side of the bladder and a second needle to receiver fluidfrom a second side of the bladder, in no particular order, orsimultaneously, for example.

FIG. 29B shows an embodiment of the deflectable fluid separator as inFIG. 29A displaced to the second side of the reservoir chamber to removefluid from the second portion 143 of the reservoir chamber. The removalof fluid from portion 143 can be achieved in many ways. For example, thedeflectable fluid separator can be displaced with injection into firstportion 141 so as to displace implantable device fluid 262 from secondportion 143. A first needle 611 and a second needle 613 can be advancedso as to extend through penetrable barrier 184 into first portion 141and into second portion 143, respectively. The first needle can injectfluid into first portion 141 to displace fluid from second portion 143.Alternatively or in combination, the second needle 613 can be aspiratedto draw fluid from second portion 143 with suction, and a fluid may bedrawn into first portion 141 through first needle 611.

FIG. 29C shows an embodiment of the deflectable fluid separator 600 asin FIG. 29B displaced to the first side of the reservoir chamber with atherapeutic fluid 260 placed in the second portion 143 of the reservoirchamber 140. The therapeutic agent 110 contained within second portion143 can be released through porous structure 153 in a manner similar toporous structure 150 as described herein. When a sufficient amount oftherapeutic agent has been released from second chamber 143 for anextended time through porous structure 153, the fluid can be removedfrom second portion 143 as described herein and a second amount oftherapeutic fluid 260 placed in first portion 141 for sustained releasefor another extended time through porous structure 151. The removal andplacement of fluid with the deflectable separator can be repeated asmany times as is helpful to treat the patient.

FIG. 30A shows an embodiment of an exchange apparatus 200 comprising avalve 700 to direct flow toward a second receiver container 704 when asample 264 of the implantable device fluid 262 has been placed in afirst receiver container 702. The valve 700 can inhibit mixing of theimplantable device fluid 262 with the therapeutic fluid 260, such thatsample fluid 264 may comprise no substantially amount of therapeuticfluid 260. The sample fluid 264 can be removed used for one or moreassays as described herein. The valve 700 may comprise one or more of aporous structure, a float valve, an annular float valve, a ball floatvalve, a flap valve, a flap valve with a float, a duckbill valve, or astopcock. The valve 700 may comprise a manual valve, or may comprise oneor more structures to automatically close or open when a sufficientamount of fluid has been placed in the first receiver container. Thereceiver container 250 may comprise the first receiver container 702 andthe second receiver container 704. The exchange apparatus 200 maycomprise one or more of the elongate structure 201, needle 270, sheath280, receiver container 250, at least one opening 258, connector 290,syringe 300, piston 302, plunger 304, chamber 310, or connector 320 asdescribed herein, for example.

The valve 700 may be configured in many ways to provide sample 264 ofimplantable device fluid 262. With elongate structure 301 introducedinto therapeutic device 100, an initial amount of implantable devicefluid 262 can be placed in first receiver container 702 with valve 700comprising a first configuration. The first configuration of valve 700can fluidically couple one or more openings 236 of elongate structure201 with the first receiver container 702 and inhibit fluidic couplingof the one or more openings of elongate structure 201 with secondreceiver container 702. When a sufficient amount of implantable devicefluid 262 has been placed in the first receiver container 702, theconfiguration valve 700 can change from the first configuration to thesecond configuration. The second configuration of valve 700 canfluidically couple the one or more openings 236 with the second receivercontainer 704 and inhibit flow to the first receiver container 702, suchthat a majority of the therapeutic fluid 260 mixed with implantabledevice fluid 262 is placed in second receiver container 704.

The valve 700 may comprise a manual valve 710 operable by a user, andmay comprise one or more of many valves known to a person of ordinaryskill in the art, for example a stopcock or other manual or automaticvalve, for example.

The sample 264 within first container 702 can be removed for analysiswith one or more of many methods or structures as described herein.

FIG. 30B shows an embodiment of an exchange apparatus 200 having a valve700 comprising a porous structure 720 to direct flow toward a secondreceiver container 704 when sample 264 of the implantable device fluid262 has been placed in first receiver container 702. The valve 720 maycomprise a substantially dry porous structure in an initial openconfiguration and a gas such as air can be situated within firstreceiver container 702. Implantable device fluid 262 accumulates in thefirst receiver container 702 and rises inside the first container 702from a distal end near the elongate structure to a proximal end of thefirst container. When a sufficient amount of implantable device fluid262 is placed on first container 702, the valve 720 contacts theimplantable device fluid 262 comprising liquid and the resistance toflow of the valve 720 increases substantially. The wetted valve 720comprises a substantially closed configuration such that the implantabledevice fluid 262 passes through a flow resistance structure 722. Theflow resistance structure 722 comprises a resistance to flow when wetthat is greater than the resistance to flow of valve 720 in the dryconfiguration and substantially less than the resistance to flow ofvalve 720 in the wet configuration, such that the dry valve 720corresponds to a substantially open configuration and the wet valve 720corresponds to a substantially closed configuration. The valve 720 andthe flow resistance structure 722 may each comprise a porous structuresimilar to the porous structure for sustained release of the therapeuticagent as described herein, for example.

The valve 720 and flow resistance structure 722 can be configured inmany ways to provide sample 264 of implantable device fluid 262 with nosubstantial portion of therapeutic fluid 260. The relative resistance toflow of the porous structure 720 when we can be substantially greaterthan the resistance to flow of the resistance structure 722 when wet,for example at least about twice, and in many embodiments at least aboutfive times the resistance to flow of the flow resistance structure. Theflow resistance structure 722 may comprise a valve that opens underpressure such as a duckbill valve or flap with a spring, for example. Abaffle 728, a channel, or other internal structure can be provided toinhibit mixing of the therapeutic fluid 260 and implantable device fluid262 with the sample fluid 264 when valve 720 is wet and comprises theclosed configuration.

FIG. 30C shows an embodiment of an exchange apparatus 200 in which valve700 comprises a float valve 730. The float valve 730 comprises a floatball 732 to direct flow toward a second receiver container 704 when asample 264 of the implantable device fluid 262 has been placed in afirst receiver container 702. The valve 732 can slide along firstcontainer 702. A valve 736 such as a flap valve or duckbill valve, forexample, can be provided to provide a resistance to flow and drive fluidinto the first receiver container 702. When the implantable device fluid262 advances into container 702, float ball 732 rises in the firstcontainer 702 until the float ball contacts a seat 734 and inhibits flowinto the first container. When float ball 732 contacts seat 734additional flow into first container 702 is inhibited and valve 736opens to allow implantable device fluid 262 into the second receivercontainer 704. The received implantable device fluid 262 mixed withtherapeutic fluid 260 may displace a gas such as air through opening258. A flow resistance structure 738 such as a second duck bill valve orbaffle can be provided near the opening to the first container toinhibit mixing of sample 264 of the first receiver container 702, forexample.

FIG. 30D shows an embodiment of an exchange apparatus 200 having a valve700 comprising a float valve 740. The float valve 740 comprises asliding annular structure 744 to direct flow toward a second receivercontainer 704 when a sample 264 of the implantable device fluid 262 hasbeen placed in first receiver container 702. The sliding annularstructure 744 may comprise an annular float ring 742 coupled to a tubehaving an opening 745 to pass fluid when the valve 740 is open. Thesheath 280 can extend over needle 270 upward from the first receivercontainer 702 to the second receiver container 704. The sheath 280 maycomprise one or more openings 236 to pass the implantable device fluid262 into the first receiver container 702 through opening 745. As thefirst receiver container 702 receives implantable device fluid 262,valve 740 rises and slides axially along sheath 280 such that a portion747 of annular structure 744 slides over one or more openings 236 toinhibit flow to the first receiver container 702.

In the closed configuration, valve 740 directs flow of the implantabledevice fluid 262 and therapeutic fluid 260 into second receivercontainer 704 through holes 748 in sheath 280. The exchange apparatusmay comprise connector 290 to couple to a syringe as described herein.

FIG. 30E shows an embodiment of an exchange apparatus 200 in which valve700 comprises a float valve 750 to direct flow toward a second receivercontainer when a sample of the implantable device fluid has been placedin a first receiver container. Float valve 750 comprises a flap 752. Theflap 750 allows sample fluid to enter the first receiver container 702through openings 757 of sheath 280, and when a sufficient amount ofsample fluid has been received with sample container 702, float valve750 closes to inhibit flow through openings 757. The implantable devicefluid 262 is passed through opening 758 into second receiver container704 when the float valve 750 is closed.

FIG. 31A1 shows an embodiment of an exchange apparatus 200 having areceiver container 250 comprising a fluid separator 800 comprising aninternal channel 822 sized to support the implantable device fluid 262with a pocket of air. The fluid separator 800 may comprise a tubularstructure 820, for example a column, having an internal dimension suchas a diameter sized to support the implantable device fluid with animmiscible separator fluid. The immiscible separator fluid may compriseone or more of an oil, a hydrophobic liquid, a gas, or air, for example.The exchange apparatus may comprise one or more of many structures asdescribed herein such as connectors to couple to a syringe and anelongate structure comprising a sheath and needle. The internal channel822 of fluid separator 800 can be fluidly coupled to openings 236 toreceive implantable device fluid 262 as described herein. The fluidreceived from the implantable device can be received in receivercontainer so as to separate the implantable device fluid 262 from thetherapeutic fluid 260. The internal channel 822 may initially comprise agas such as air which can be displaced through opening 258 of receivercontainer 250.

While the exchange apparatus can be used in many ways with an immiscibleseparator fluid such as a gas comprising air, in many embodiments thetherapeutic fluid 260 is first drawn into a syringe 300, and then theimmiscible separator fluid such as air drawn into syringe 300. Thesyringe 300 can be coupled to the exchange apparatus 200 with thetherapeutic fluid supported with the immiscible separator fluid such asair within the container, for example. In many embodiments, the barrelof the syringe comprises an inner diameter sized such that thetherapeutic fluid 260 can remain free standing within the barrel of thesyringe and may be supported with air, such that the air can be injectedinto the implantable device before the air is injected. The implantabledevice may comprise a maximum cross-sectional dimension, for example amaximum diameter, such the implantable device fluid can be supported anddisplaced with the immiscible separator fluid 810 placed in the lowerportion of the reservoir chamber near porous structure 150. Injection ofthe immiscible separator fluid 810 displaces implantable device fluid262 through one or more openings 236 of sheath 280 and upward intochannel 822. When a substantial portion of the implantable device fluidhas been displaced from the reservoir chamber, for example with air, thetherapeutic fluid 260 can enter the reservoir chamber such that theimplantable device fluid 262 remains substantially separated from thetherapeutic fluid 260 introduced into the reservoir chamber.

The separator fluid 810 may comprise a miscible separator fluid, forexample saline or other liquid capable of mixing with the therapeuticfluid 260 and the implantable device fluid 262, and the separator fluid810 may comprise a sufficient volume so as to inhibit mixing of thetherapeutic fluid 260 with the implantable device fluid 262. In manyembodiments, the separator fluid 810 comprises a fluid not miscible withthe therapeutic fluid 260 and implantable device fluid 262, each ofwhich may comprise substantial amounts of water. The immiscibleseparator fluid 810 can inhibit mixing of the implantable device fluid262 and the therapeutic fluid 260 with the separator fluid 810, suchthat the separator fluid 810 may comprise a barrier and inhibit mixingof the components of the implantable device fluid 262 with components ofthe therapeutic fluid 260.

FIG. 31A2 shows an embodiment of the exchange apparatus 200 of FIG. 31A1having the implantable device fluid 262 supported with a pocket ofimmiscible separator fluid 810 such as air 812, so as to separate theimplantable device fluid 262 from the therapeutic fluid 260. Aninterface 818 extends between the immiscible separator fluid 810 and theimplantable device fluid 262. An interface 814 extends between theimmiscible separator fluid 810 and the therapeutic fluid 260. In manyembodiments, immiscible separator fluid 810 comprises a gas, andimplantable device fluid 262 and therapeutic fluid 260 each compriseliquid such that interface 814 comprises a meniscus and interface 818comprise a meniscus.

FIG. 31B1 shows an embodiment of an exchange apparatus 200 having afluid separator 800 comprising an internal channel having a firstportion 852 sized to support the implantable device fluid with a pocketof an immiscible separator fluid air and a second portion 854 sized topass an immiscible separator fluid such as air through the implantabledevice fluid. The first portion may comprise a volume approximating thevolume of the reservoir chamber, for example. The exchange apparatus maycomprise one or more of the structures of the exchange apparatus 200 asdescribed herein, for example receiver container 200 and container wall252 may have dimensions so as to define the first portion 852 and thesecond portion 854.

FIG. 31B2 shows an embodiment of the exchange apparatus of FIG. 31B1having the first portion 852 supporting the implantable device fluid 262with the immiscible separator fluid 810 such as air 812. The tip 212 ofneedle 270 may extend to the distal end of the reservoir chamber 140such that the bubble forms at the distal end of the reservoir toincrease exchange efficiency, for example. The reservoir chamber 140 andthe first portion 852 may comprise immiscible separator fluid 810 suchas air 812.

FIG. 31B3 shows an embodiment of the exchange apparatus of FIGS. 31B1and 31B2 having the first portion 852 supporting the implantable devicefluid 262 with the pocket of immiscible separator fluid 810 andtherapeutic fluid 260, and the second portion containing the implantabledevice fluid. As additional gas such as air moves upward from the firstportion 852 to the second portion 854, the immiscible separator fluidcomprising a gas such as air forms bubbles in second portion 854 havingthe increased inner dimensions and the bubble can travel upward toescape through opening 258. The first portion 852 and the second portion854 may each comprise an annular channel having an inner dimensiondetermined by the outside diameter of needle 270, for example. Theincreased outer dimension of the annular channel of the second portion854 allows bubbles to form in the implantable device fluid 262 containedin the second portion such that the bubbles can rise and escape throughvalve 258.

FIG. 31C shows an embodiment of exchange apparatus 200 coupled to asyringe 300 comprising a separator structure 860 to inject a separationfluid 810 and a therapeutic fluid into therapeutic device to collect asample 264 of implantable device fluid 262. The separator structure 860may comprise one or more of a piston 864, a plunger, a disk or a plughaving one or more holes 862. The holes 862 may comprise a sufficientresistance to flow such that the piston 864 moves downward toward theelongate structure 201 when the piston 302 is advanced.

The piston 864 can displace the immiscible separator fluid 810comprising air, such that the immiscible separator fluid 810 isdisplaced into reservoir chamber 140 and forms an interfacial boundary816. The interfacial boundary 816 moves toward sheath 280 as theimplantable device fluid is displaced with the immiscible separatorfluid 810. When the piston 864 has advanced a sufficient distance,movement of piston 864 along the cylinder barrel is inhibited, and thetherapeutic fluid 260 is displaced through the one or more holes 862with piston 302. The displaced therapeutic fluid 260 is placed inreservoir chamber 140, for example with injection through the needle.The immiscible separator fluid 810 is displaced with therapeutic fluid260 such that the immiscible separator fluid 810 enters receivercontainer 250.

In many embodiments the receiver container 250 comprises a volume thatis at least the volume of the injected material comprising therapeuticfluid 260 and immiscible separator fluid 810, such that the volume ofthe receiver container 250 is sufficient to retain the implantabledevice fluid 262 and the immiscible separator fluid 810. The volume ofimmiscible separator fluid 810 injected with the therapeutic fluid canbe less than, approximately the same as, or greater than the volume ofthe therapeutic agent injected. In many embodiments, the immiscibleseparator fluid 810 comprises a volume sufficient to separate thetherapeutic fluid from the implantable device fluid and which issubstantially less than the volume of the reservoir chamber. Forexample, the amount of immiscible separator fluid 810 may comprise avolume that is sufficient to form a bubble within the reservoir chamber140 and that is substantially less than the volume of the volume ofreservoir chamber 140.

The receiver container 250 can be configured in many ways to receive theimplantable device fluid 262 and the immiscible separator fluid 810. Forexample, the receiver container 250 may comprise the inside dimensionsufficient to support the implantable device fluid with the immiscibleseparator fluid along a majority of the length of the receiver container250. Alternatively, the first portion 852 of the receiver container maycomprise the inside dimension sufficient to support the implantabledevice fluid 262 and the second portion 854 of the receiver containermay comprise the inside dimension sufficiently large so as to pass theimmiscible separator fluid 810 through the implantable device fluid. Aperson or ordinary skill in the art can determine the internaldimensions of the first portion and the second portion based on theteachings of the present disclosure.

FIG. 32 shows an embodiment of an exchange apparatus coupled to syringe300 to draw therapeutic fluid into the implantable device from thecontainer 250. The implantable device fluid 262 can be drawn from thereservoir chamber in one or more of many ways, for example with syringeso to provide aspirating suction of the implantable device fluid fromthe implantable device into the syringe. As the needle 272 extendsthrough penetrable barrier 184 so as to provide a seal and the porousstructure 150 comprises a resistance to flow of components of the eye,the movement of the implantable device fluid 262 into the chamber ofsyringe 300 results in therapeutic fluid 260 moving from chamber 250through the one or more openings 289 in sheath 280. Air at approximatelyatmospheric pressure can move into container 250 to urge and displacethe therapeutic fluid 260 into the reservoir chamber when theimplantable device fluid 262 is drawn with the syringe.

FIG. 33 shows an embodiment of a curved needle 270 of an exchangeapparatus to direct therapeutic fluid 260 toward a wall 260 of acontainer 230 of the reservoir chamber 240. The curved needle can beplaced near the porous structure 150 and may result in a reproducibleflow pattern of the therapeutic fluid 260 placed in the container. Thereproducible flow pattern provided by the curved needle 270 can providea consistent flow pattern over porous structure 150 and may provide amore uniform amount of bolus through porous structure 150.

FIG. 34 shows an embodiment of a covering 870 on a porous structure of atherapeutic device to inhibit bolus release when the therapeutic fluidis introduced. The covering 870 can inhibit bolus release when theneedle is oriented toward the porous structure 150 and the covering 870,for example.

FIG. 35 shows an embodiment of a first exchange apparatus 200A coupledto a double barrel syringe 300 to exchange a first exchange fluid 900with the implantable device fluid 262, and a second exchange apparatus200B to exchange the first exchange fluid placed in the therapeuticdevice with therapeutic fluid 260. The first exchange fluid 900 maycomprise the separator fluid 810 as described herein. The first exchangefluid 900 may comprise water, for example phosphate buffered saline(hereinafter “PBS”). Alternatively, the first exchange fluid maycomprise an immiscible separator fluid as described herein.

The first exchange apparatus 200A and the second exchange apparatus 200Bmay each comprise many of the structures of exchange apparatus 200 asdescribed herein. For example, the first exchange apparatus 200A and thesecond exchange apparatus 200B may each comprise the elongate structure201 and receiver container 250 as described herein. The double barrelsyringe 300 may comprise the therapeutic fluid and the first exchangefluid 900. The double barrel syringe 300 may comprise a first chamber910 containing the first exchange fluid 900 and a second chamber 920containing the therapeutic fluid 260. The first chamber 910 may becoupled to a first piston 912 and plunger 914 having a first length. Thesecond chamber 920 may be coupled to a second piston 922 and plunger 924having a second length. The first length can be longer than the secondlength to that the contents of the first chamber are injected before thesecond chamber. The first exchange apparatus 200A can be connected tothe syringe 300 and the elongate structure 201 inserted into theimplantable device as described herein, and the first plunger advancedso as to displaced the implantable device fluid 262 from the reservoirchamber 140 with the first exchange fluid 900. The first exchangeapparatus 200A can be removed from therapeutic device implanted in theeye. The first exchange apparatus 200A can be disconnected from thesyringe 300, and the second exchange apparatus 200B connected to thesyringe 300 and advanced into the therapeutic device 100. The secondplunger 924 can be advanced to displace the first exchange fluid 900from the reservoir chamber 140 of the implantable device with thetherapeutic fluid 260 as described herein.

In many embodiments, one or more of the components of the first exchangeapparatus 200A and the second exchange apparatus 200B can be combinedfor use with the double barrel syringe so that the first exchange fluidand the therapeutic fluid can each be exchanged sequentially when theexchange apparatus 200 is placed in the implantable device and withoutremoving the exchange apparatus from the implanted device. For example,the exchange apparatus 200 may comprise the first receiver 702 containerto receive the implantable device fluid and the second receivercontainer 704 as described herein to receive the first exchange fluid,and the first receiver container and the second receiver container canbe coupled to one or more valves as described herein such that theimplantable device fluid 262 is directed to the first receiver containerwhen the valve comprises a first configuration and the first exchangefluid is directed to the second receiver container when the valvecomprises a second configuration as described herein.

Experimental

FIG. 36 shows an experimental test apparatus. The test apparatuscomprised an injector coupled to a bi-needle exchange apparatus 200 toinject a therapeutic fluid comprising a therapeutic agent into a testimplantable device 100. The therapeutic fluid comprised a 100 mg/mLformulation of ranibizumab prepared in accordance with U.S. Pat. Pub.No. 2010/0015157, entitled “Antibody Formulations”, the full disclosureof which is incorporated by reference. The injected formulationcomprised a density at least about 1 greater than the fluid of theimplantable device, which comprised saline.

The therapeutic fluid was injected through the penetrable barriercomprising a septum of silicone elastomer. The injector needle wasapproximately 33 gauge and coupled to a syringe and positioned below thereceiver needle. The receiver needle received liquid from theimplantable device and extended upward to a receiver container. Axis ofthe injector needle 202 and the axis of the implantable device 100A wereoriented to obtain samples. The reservoir chamber of the implantabledevice comprised about 25 μL, and about 50 μL were injected. Theorientation of the axes varied from 0 degrees (horizontal) 45 degreesaway from horizontal. At the −45 degree orientation the penetrablebarrier was located above the reservoir chamber and the opening to thereceiver needle located above the opening to the injector needle.

FIG. 37 shows experimental results obtained with the test apparatus ofFIG. 36. The refill efficiency corresponded to the amount of therapeuticfluid placed in the reservoir chamber of the implantable device when the50 uL had been injected. For 0 degrees, the efficiency was about 80%.The efficiency increased with the angle to about 95% at −45 degrees.

Table 2 shows device angles and fill efficiencies corresponding to thevalues in the graph of FIG. 37.

Device Angle (+/−sign arbitrary) Refill Efficiency 0 77.5 15 88.3 2588.9 35 94 45 94

A concentric needle device was also tested and provided similar results.

Pressure studies have been conducted with the injector apparatus havingthe plurality of openings. The sheath comprised polyimide placed over a33 Gauge needle. A first pressure gauge was coupled to a syringe on theinput side of the needle, and a second pressure gauge was coupled to theimplantable device reservoir chamber where the porous structure is shownabove. The input pressure to the syringe of 12 N produced a pressure of85 pounds per square inch (hereinafter “psi”) into the needle andimplantable device chamber had a pressure of about 45 psi. This amountof input pressure corresponds to a clinically acceptable exchange timeof about 5 seconds, for example.

Additional experiments can be conducted by a person of ordinary skill inthe art based on the teachings described herein, for example experimentswith an exchange apparatus comprising a polyimide sheath comprising aplurality of openings over a needle as described herein.

Additional experiments can be conducted with one or more of many releasecontrol mechanisms to determine the resistance to flow of the releasecontrol mechanism suitable for use in accordance with embodimentsdescribed herein. For example, studies can be conducted with porousstructures of varying dimensions, release rates, and manufacturingprocesses, in order to measure the flow through the frits with pressureso as to determine the resistance to flow.

While the exemplary embodiments have been described in some detail, byway of example and for clarity of understanding, those of skill in theart will recognize that a variety of modifications, adaptations, andchanges may be employed.

TABLE 1A Therapeutic Agent List Molecular Generic Name Brands(Companies) Category Indication Weight 2-Methoxyestradiol (PalomaPharmaceuticals) Angiogenesis inhibitors AMD analogs 3-aminothalidomide13-cis retinoic Accutane TM (Roche acid Pharmaceuticals) A0003 (AqumenBioPharmaceuticals) A0003 AMD A5b1 integrin (Jerini Ophthalmic);(Ophthotech) Inhibitors of a5b1 AMD inhibitor integrin AbarelixPlenaxis ™ (Praecis Pharmaceuticals) Anti-Testosterone For palliativetreatment of advanced 37731 Agents; prostate cancer. AntineoplasticAgents Abatacept Orencia ™ (Bristol-Myers Squibb) Antirheumatic AgentsFor the second line reduction of the signs 37697 and symptoms ofmoderate-to-severe active rheumatoid arthritis, inducing major clinicalresponse, slowing the progression of structural damage, and improvingphysical function in adult patients who have Abciximab ReoPro ™;ReoPro ™ (Centocor) Anticoagulants; For treatment of myocardialinfarction, 42632 Antiplatelet Agents adjunct to percutaneous 81oronaryintervention, unstable angina ABT-578 (Abbott Laboratories) LimusImmunophilin Binding Compounds Acetonide Adalimumab Humira ™ (AbbottLaboratories) Antirheumatic Agents; Uveitis, AMD 25645 ImmunomodulatoryAgents Aldesleukin Proleukin ™; Proleukin ™ (Chiron AntineoplasticAgents For treatment of adults with metastatic 61118 Corp) renal cellcarcinoma Alefacept Amevive ™ Immunomodulatory For treatment of moderateto severe 42632 Agents; chronic plaque psoriasis ImmunosuppressiveAgents Alemtuzumab Campath ™; Campath ™ (ILEX Antineoplastic Agents Fortreatment of B-cell chronic 6614 Pharmaceuticals LP); MabCampath ™lymphocytic leukemia Alpha-1- Aralast ™ (Baxter); Prolastin ™ EnzymeReplacement For treatment of panacinar emphysema 28518 proteinase(Talecris Biotherapeutics C formerly Agents inhibitor Bayer) AlteplaseActivase ™ (Genentech Inc) Thrombolytic Agents For management of acutemyocardial 54732 infarction, acute ischemic strok and for lysis of acutepulmonary emboli AMG-1470 Anakinra Kineret ™ (Amgen Inc)Anti-Inflammatory For the treatment of adult rheumatoid 65403 Agents,Non-Steroidal; arthritis. Antirheumatic Agents; Immunomodulatory AgentsAnecortave acetate Angiostatin Anistreplase Eminase ™ (Wulfing PharmaGmbH) Thrombolytic Agents For lysis of acute pulmonary emboli, 54732intracoronary emboli and management of myocardial infarctionAnti-angiogenesis (Eyecopharm) Anti-angiogenesis AMD peptides peptidesAnti-angiogenesis (TRACON Pharma) Anti-angiogenesis AMD antibodies,antibodies TRC093, TRC105 Anti-angiogeric Icon-1 ™ (Iconic Therapeutics)Anti-angiogeric AMD bifunctional bifunctional protein, protein Icon-1Anti-endothelial growth factor Antihemophilic Advate ™; Alphanate ™;Bioclate ™; Coagulants; For the treatment of hemophilia A, von 70037Factor Helixate ™; Helixate FS ™; Hemofil Thrombotic Willebrand diseaeand Factor XIII M ™; Humate-P ™; Hyate: C ™; Agents deficiencyKoate-HP ™; Kogenate ™; Kogenate FS ™; Monarc-M ™; Monoclate-P ™;ReFacto ™; Xyntha ™ Antithymocyte Genzyme); Thymoglobulin ™Immunomodulatory For prevention of renal transplant 37173 globulin(SangStat Medical Agents rejection Anti-hypertensive (MacuCLEAR)Anti-hypertensive AMD MC1101 MC1101 Anti-platelet devired growth factorAnti-VEGF (Neurotech); Avastin ™ (NeoVista) Anti-VEGF AMD AP23841(Ariad) Limus Immunophilin Binding Compounds ARC1905 OphthotechComplement Cascade Inhibitor (Factor C5) Aprotinin Trasylol ™Antifibrinolytic For prophylactic use to reduce 90569 Agentsperioperative blood loss and the need for blood transfusion in patientsundergoing cardiopulmonary bypass in the course of coronary arterybypass graft surgery who are at an increased risk for blood loss andblood transfusio Arcitumomab CEA-Scan ™ Diagnostic Agents; For imagingcolorectal tumors 57561 Imaging Agents Asparaginase Elspar ™ (Merck &Co. Inc) Antineoplastic Agents For treatment of acute lympocytic 132.118leukemia and non-Hodgkins lymphoma Axitinib Tyrosine Kinase 386Inhibitors Basiliximab Simulect ™ (Novartis Immunomodulatory Forprophylactic treatment of kidney 61118 Pharmaceuticals) Agents;transplant rejection Immunosuppressive Agents Becaplermin Regranex ™;Regranex ™ (OMJ Anti-Ulcer Agents; For topical treatment of skin ulcers(from 123969 Pharmaceuticals) Topical diabetes) Bevacizumab Avastin ™;Avastin ™ (Genentech Inc) Antiangiogenesis For treatment of metastaticcolorectal 27043 Agents; cancer Antineoplastic Agents BivalirudinAngiomax ™; Angiomax ™ (Medicines Anticoagulants; For treatment ofheparin-induced 70037 Co or MDCO); Angiox ™ Antithrombotic Agentsthrombocytopenia Bortezomib Proteosome Inhibitors Bosutinib TyrosineKinase 530 Inhibitors Botulinum BOTOX ™ (Allegran Inc); BOTOXAnti-Wrinkle Agents; For the treatment of cervical dystonia in 23315Toxin Cosmetic ™ (Allegran Inc); Botox ™; Antidystonic Agents; adults todecrease the severity of Type A Dysport ™ Neuromuscular Blockingabnormal head position and neck pain Agents associated with cervicaldystonia. Also for the treatment of severe primary axillaryhyperhidrosis that is inadequately managed with topical BotulinumMyobloc ™ (Solstice Neurosciences); Antidystonic Agents For thetreatment of patients with cervical 12902 Toxin Neurobloc ™ (SolsticeNeurosciences) dystonia to reduce the severity of Type B abnormal headposition and neck pain associated with cervical dystonia. C5 inhibitor(Jerini Ophthalmic); (Ophthotech) Inhibitors of C5 AMD Cal101 CalistogaPI3Kdelta Inhibitor AMD, DME Canstatin Capromab ProstaScint ™ (CytogenCorp) Imaging Agents For diagnosis of prostate cancer and 84331detection of intra-pelvic metastases Captopril ACE Inhibitors CCI-779(Wyeth) Limus Immunophilin Binding Compounds Cediranib Tyrosine Kinase450 Inhibitors Celecoxib Cyclooxygenase Inhibitors CetrorelixCetrotide ™ Hormone Antagonists; For the inhibition of premature LHsurges 78617 Infertility Agents in women undergoing controlled ovarianstimulation Cetuximab Erbitux ™; Erbitux ™ (ImClone AntineoplasticAgents For treatment of metastatic colorectal 42632 Systems Inc) cancer.Choriogo- Novarel ™; Ovidrel ™; Pregnyl ™; Fertility Agents; For thetreatment of female infertility 78617 nadotropin Profasi ™ Gonadotropinsalfa Cilary (Neurotech) Cilary neurotrophic AMD neurotrophic factorfactor Coagulation Benefix ™ (Genetics Institute) Coagulants; ThromboticFor treatment of hemophilia (Christmas 267012 Factor IX Agents disease).Coagulation NovoSeven ™ (Novo Nordisk) Coagulants; Thrombotic Fortreatment of hemorrhagic 54732 factor VIIa Agents complications inhemophilia A and B Colchicines Collagenase Cordase ™; Santyl ™ (AdvanceAnti-Ulcer Agents; For treatment of chronic dermal ulcers 138885Biofactures Corp); Xiaflextm ™ Topical and severe skin burns Complement(Optherion); (Taligen Therapeutics) Complement factor H AMD, GeographicAtrophy factor H recombinant recombinant Compstatin (PotentiaPharmaceuticals) Complement Factor C3 AMD derivative Inhibitors;Compstatin peptide, Derivative Peptides POT-4 Corticotropin ACTH ™;Acethropan ™; Acortan ™; Diagnostic Agents For use as a diagnostic agentin the 33927 Acthar ™; Exacthin ™; H.P. Acthar screening of patientspresumed to have Gel ™; Isactid ™; Purified cortrophin adrenocorticalinsufficiency. gel ™; Reacthin ™; Solacthyl ™; Tubex CosyntropinCortrosyn ™; Synacthen depot ™ Diagnostic Agents For use as a diagnosticagent in the 33927 screening of patients presumed to have adrenocorticalinsufficiency. Cyclophilins Limus Immunophilin Binding CompoundsCyclosporine Gengraf ™ (Abbott labs); Neoral ™ Antifungal Agents; Fortreatment of transplant rejection, 32953 (Novartis); Restasis ™;Restasis ™ Antirheumatic Agents; rheumatoid arthritis, severe psoriasis(Allergan Inc); Sandimmune ™ Dermatologic Agents; (Novartis); Sangcya ™Enzyme Inhibitors; Immunomodulatory Agents; Immunosuppressive AgentsDaclizumab Zenapax ™ (Hoffmann-La Roche Inc) Immunomodulatory Forprevention of renal transplant 61118 Agents; rejection; UveitisImmunosuppressive Agents Darbepoetin Aranesp ™ (Amgen Inc.) AntianemicAgents For the treatment of anemia (from renal 55066 alfa transplants orcertain HIV treatment) Dasatinib Tyrosine Kinase 488 InhibitorsDefibrotide Dasovas ™; Noravid ™; Prociclide ™ Antithrombotic AgentsDefibrotide is used to treat or prevent a 36512 failure of normal bloodflow (occlusive venous disease, OVD) in the liver of patients who havehad bone marrow transplants or received certain drugs such as oralestrogens, mercaptopurine, and many others. Denileukin Ontak ™Antineoplastic Agents For treatment of cutaneous T-cell 61118 diftitoxlymphoma Desmopressin Adiuretin ™; Concentraid ™; Stimate ™ AntidiureticAgents; For the management of primary nocturnal 46800 Hemostatics; Renalenuresis and indicated as antidiuretic Agents replacement therapy in themanagement of central diabetes insipidus and for the management of thetemporary polyuria and polydipsia following head trauma or surgery inthe pitu Dexamethasone Ozurdex ™ (Allergan) Glucocorticoid DME,inflammation, macular edema 392 following branch retinal vein occlusion(BRVO) or central retinal vein occlusion (CRVO) DiclofenacCyclooxygenase Inhibitors Dithiocarbamate NFκB Inhibitor Dornase AlfaDilor ™; Dilor-400 ™; Lufyllin ™; Enzyme Replacement For the treatmentof cystic fibrosis. 7656 Lufyllin-400 ™; Neothylline ™; Agents (doublePulmozyme ™ (Genentech Inc) strand) Drotrecogin Xigris ™; Xigris ™ (EliLilly & Co) Antisepsis Agents For treatment of severe sepsis 267012 alfaEculizumab Soliris ™; Soliris ™ (Alexion Complement Cascade AMD 188333Pharmaceuticals) Inhibitor (Factor C5) Efalizumab Raptiva ™; Raptiva ™(Genentech Inc) Immunomodulatory For the treatment of adult patientswith 128771 Agents; moderate to severe chronic plaque Immunosuppressivepsoriasis, who are candidates for Agents phototherapy or systemictherapy. Endostatin Enfuvirtide Fuzeon ™; Fuzeon ™ (Roche Anti-HIVAgents; HIV For treatment of HIV AIDS 16768 Pharmaceuticals) FusionInhibitors Epoetin alfa Epogen ™ (Amgen Inc.); Epogin ™ AntianemicAgents For treatment of anemia (from renal 55066 (Chugai); Epomax ™(Elanex); transplants or certain HIV treatment) Eprex ™ (Janssen-Cilag.Ortho Biologies LLC); NeoRecormon ™ (Roche); Procrit ™ (Ortho Biotech);Recormon ™ (Roche) Eptifibatide Integrilin ™; Integrilin ™ (MillenniumAnticoagulants; For treatment of myocardial infarction and 7128 Pharm)Antiplatelet Agents; acute coronary syndrome. Platelet AggregationInhibitors Erlotinib Tyrosine Kinase 393 Inhibitors Etanercept Enbrel ™;Enbrel ™ (Immunex Corp) Antirheumatic Agents; Uveitis, AMD 25645Immunomodulatory Agents Everolimus Novartis Limus Immunophilin AMDBinding Compounds, mTOR Exenatide Byetta ™; Byetta ™ (Amylin/Eli Lilly)Indicated as adjunctive therapy to 53060 improve glycemic control inpatients with Type 2 diabetes mellitus who are taking metformin, asulfonylurea, or a combination of both, but have not achieved adequateglycemic control. FCFD4514S Genentech/Roche Complement Cascade AMD,Geographic Atrophy Inhibitor (Factor D) Felypressin Felipresina ™[INN-Spanish]; Renal Agents; For use as an alternative to adrenaline as46800 Felipressina ™ [DCIT]; Felypressin ™ Vasoconstrictor Agents a91ocalizing agent, provided that local [USAN:BAN:INN]; Felypressine ™ischaemia is not essential. [INN-French]; Felypressinum ™ [INN- Latin];Octapressin ™ Fenretinide Sirion/reVision Therapeutics Binding ProteinAMD, Geographic Atrophy Antagonist for Oral Vitamin A FilgrastimNeupogen ™ (Amgen Inc.) Anti-Infective Agents; Increases leukocyteproduction, for 28518 Antineutropenic Agents; treatment in non-myeloidImmunomodulatory cancer, neutropenia and bone marrow Agents transplantFK605-binding Limus Immunophilin proteins, Binding Compounds FKBPsFluocinolone Retisert ™ (Bausch & Lomb); Iluvien ™ GlucocorticoidRetinal inflammation, diabetic macular 453 Acetonide (Alimera Sciences,Inc.) edema Follitropin Follistim ™ (Organon); Gonal F ™; FertilityAgents For treatment of female infertility 78296 beta Gonal-F ™Fumagillin Galsulfase Naglazyme ™; Naglazyme ™ Enzyme Replacement Forthe treatment of adults and children 47047 (BioMarin Pharmaceuticals)Agents with Mucopolysaccharidosis VI. Gefitinib Tyrosine Kinase 447Inhibitors Gemtuzumab Mylotarg ™; Mylotarg ™ (Wyeth) AntineoplasticAgents For treatment of acute myeloid leukemia 39826 ozogamicinGlatiramer Copaxone ™ Adjuvants, For reduction of the frequency ofrelapses 29914 Acetate Immunologic; in patients with Relapsing-RemittingImmunosuppressive Multiple Sclerosis. Agents Glucagon GlucaGen ™(NovoNordisk); Antihypoglycemic For treatment of severe hypoglycemia,54009 recombinant Glucagon ™ (Eli Lilly) Agents also used ingastrointestinal imaging Goserelin Zoladex ™ Antineoplastic Agents;Breast cancer; Prostate carcinoma; 78617 Antineoplastic Agents,Endometriosis Hormonal Human Serum Albutein ™ (Alpha Therapeutic Corp)Serum substitutes For treatment of severe blood loss, 39000 Albuminhypervolemia, hypoproteinemia Hyaluronidase Vitragan ™; Vitrase ™;Vitrase ™ (Ista Anesthetic Adjuvants; For increase of absorption anddistribution 69367 Pharma) Permeabilizing Agents of other injected drugsand for rehydration Ibritumomab Zevalin ™ (IDEC Pharmaceuticals)Antineoplastic Agents For treatment of non-Hodgkin's lymphoma 33078Idursulfase Elaprase ™ (Shire Pharmaceuticals) Enzyme Replacement Forthe treatment of Hunter syndrome in 47047 Agents adults and childrenages 5 and older. Imatinib Tyrosine Kinase AMD, DME 494 InhibitorsImmune globulin Civacir ™; Flebogamma ™ (Instituto Anti-Infectives; Fortreatment of immunodeficiencies, 42632 Grifols SA); Gamunex ™ (TalecrisImmunomodulatory thrombocytopenic purpura, Kawasaki Biotherapeutics)Agents disease, gammablobulinemia, leukemia, bone transplant InfliximabRemicade ™ (Centocor Inc) Immunomodulatory Uveitis, AMD 25645 Agents;Immunosuppressive Agents Insulin Glargine Lantus ™ Hypoglycemic AgentsFor treatment of diabetes (type I and II) 156308 recombinant InsulinLyspro Humalog ™ (Eli Lily); Insulin Lispro Hypoglycemic Agents Fortreatment of diabetes (type I and II) 154795 recombinant (Eli Lily)Insulin Novolin R ™ (Novo Nordisk) Hypoglycemic Agents For treatment ofdiabetes (type I and II) 156308 recombinant Insulin, porcine Iletin II ™Hypoglycemic Agents For the treatment of diabetes (type I and 156308 II)Interferon Interferon Roferon A ™ (Hoffmann-La Roche AntineoplasticAgents; For treatment of chronic hepatitis C, hairy 57759 Alfa-2a, Inc);Veldona ™ (Amarillo Antiviral Agents cell leukemia, AIDS-relatedKaposi's Recombinant Biosciences) sarcoma, and chronic myelogenousleukemia. Also for the treatment of oral warts arising from HIVinfection. Interferon Intron A ™ (Schering Corp) Antineoplastic Agents;For the treatment of hairy cell leukemia, 57759 Alfa-2b, AntiviralAgents; malignant melanoma, and AIDS-related RecombinantImmunomodulatory Kaposi's sarcoma. Agents Interferon Advaferon ™;Infergen ™ (InterMune Antineoplastic Agents; For treatment of hairy cellleukemia, 57759 alfacon-1 Inc) Antiviral Agents; malignant melanoma, andAIDS-related Immunomodulatory Kaposi's sarcoma Agents InterferonWellferon ™ (GlaxoSmithKline) Antiviral Agents; For treatment ofvenereal or genital warts 57759 alfa-n1 Immunomodulatory caused by theHuman Papiloma Virus Agents Interferon Alferon ™ (Interferon SciencesInc.); Antineoplastic Agents; For the intralesional treatment of 57759alfa-n3 Alferon LDO ™; Alferon N Injection Antiviral Agents; refractoryor recurring external Immunomodulatory condylomata 95cuminate. AgentsInterferon Betaseron ™ (Chiron Corp) Antiviral Agents; For treatment ofrelapsing/remitting 57759 beta-1b Immunomodulatory multiple sclerosisAgents Interferon Actimmune ™; Actimmune ™ Antiviral Agents; Fortreatment of Chronic granulomatous 37835 gamma-1b (InterMune Inc)Immunomodulatory disease, Osteopetrosis Agents Lapatinib Tyrosine Kinase581 Inhibitors Lepirudin Refludan ™ Anticoagulants; For the treatment ofheparin-induced 70037 Antithrombotic Agents; thrombocytopeniaFibrinolytic Agents Lestaurtinib Tyrosine Kinase 439 InhibitorsLeuprolide Eligard ™ (Atrix Labs/QLT Inc) Anti-Estrogen Agents; Fortreatment of prostate cancer, 37731 Antineoplastic Agents endometriosis,uterine fibroids and premature puberty Lutropin alfa Luveris ™ (Serono)Fertility Agents For treatment of female infertility 78617 MecaserminIncrelex ™; Increlex ™ (Tercica); Iplex For the long-term treatment ofgrowth 154795 failure in pediatric patients with Primary IGFD or with GHgene deletion who have developed neutralizing antibodies to GH. It isnot indicated to treat Secondary IGFD resulting from GH deficiency,malnutrition, hypoth Menotropins Repronex ™ Fertility Agents Fortreatment of female infertility 78617 Methotrexate ImmunomodulatoryUveitis, DME mTOR inhibitors Muromonab Orthoclone OKT3 ™ (Ortho Biotech)Immunomodulatory For treatment of organ transplant 23148 Agents;recipients, prevention of organ rejection Immunosuppressive AgentsNatalizumab Tysabri ™ Immunomodulatory For treatment of multiplesclerosis. 115334 Agents Nepafenac Cyclooxygenase Inhibitors NesiritideNatrecor ™ Cardiac drugs For the intravenous treatment of patients118921 with acutely decompensated congestive heart failure who havedyspnea at rest or with minimal activity. Nilotinib Tyrosine Kinase 530Inhibitors NS398 Cyclooxygenase Inhibitors Octreotide Atrigel ™;Longastatin ™; Anabolic Agents; For treatment of acromegaly and 42687Sandostatin ™; Sandostatin LAR ™; Antineoplastic reduction of sideeffects from cancer Sandostatin LAR ™ (Novartis) Agents, Hormonal;chemotherapy Gastrointestinal Agents; Hormone Replacement AgentsOmalizumab Xolair ™ (Genentech Inc) Anti-Asthmatic Agents; For treatmentof asthma caused by 29596 Immunomodulatory allergies Agents OprelvekinNeumega ™; Neumega ™ (Genetics Coagulants; Increases reduced plateletlevels due to 45223 Institute Inc) Thrombotics chemotherapy OspALYMErix ™ (SmithKline Beecham) Vaccines For prophylactic treatment ofLyme 95348 lipoprotein Disease OT-551 (Othera) Anti-oxidant eyedrop AMDOxytocin Oxytocin ™ (BAM Biotech); Pitocin ™ Anti-tocolytic Agents; Toassist in labor, elective labor induction, 12722 (Parke-Davis);Syntocinon ™ (Sandoz) Labor Induction Agents; uterine contractioninduction Oxytocics Palifermin Kepivance ™ (Amgen Inc) AntimucositisAgents For treatment of mucositis (mouth sores) 138885 PalivizumabSynagis ™ Antiviral Agents For treatment of respiratory diseases 63689casued by respiratory syncytial virus Panitumumab Vectibix ™; Vectibix ™(Amgen) Antineoplastic Agents For the treatment of EGFR-expressing,134279 metastatic colorectal carcinoma with disease progression on orfollowing fluoropyrimidine-, oxaliplatin-, and irinotecan- containingchemotherapy regimens. PDGF inhibitor (Jerini Ophthalmic); (Ophthotech)Inhibitors of PDGF AMD PEDF (pigment epithelium derived factor)Pegademase Adagen ™ (Enzon Inc.) Enzyme Replacement For treatment ofadenosine deaminase 36512 bovine Agents deficiency Pegaptanib Macugen ™Oligonucleotide For the treatment of neovascular (wet) 103121age-related macular degeneration. Pegaspargase Oncaspar ™ (Enzon Inc)Antineoplastic Agents For treatment of acute lymphoblastic 132.118leukemia Pegfilgrastim Neulasta ™ (Amgen Inc.) Anti-Infective Agents;Increases leukocyte production, for 28518 Antineutropenic Agents;treatment in non-myeloid cancer, Immunomodulatory neutropenia and bonemarrow transplant Agents Peginterferon Pegasys ™ (Hoffman-La Roche Inc)Antineoplastic Agents; For treatment of hairy cell leukemia, 57759alfa-2a Antiviral Agents; malignant melanoma, and AIDS-relatedImmunomodulatory Kaposi's sarcoma. Agents Peginterferon PEG-Intron(Schering Corp); Unitron Antineoplastic Agents; For the treatment ofchronic hepatitis C in 57759 alfa-2b PEG ™ Antiviral Agents; patientsnot previously treated with Immunomodulatory interferon alpha who havecompensated Agents liver disease and are at least 18 years of age.Pegvisomant Somavert ™ (Pfizer Inc) Anabolic Agents; For treatment ofacromegaly 71500 Hormone Replacement Agents Pentoxifylline PerindozrilACE Inhibitors Pimecrolimus Limus Immunophilin Binding Compounds PKC(protein kinase C) inhibitors POT-4 Potentia/Alcon Complement CascadeAMD Inhibitor (Factor C3) Pramlintide Symlin ™; Symlin ™ (Amylin For themealtime treatment of Type I and 16988 Pharmaceuticals) Type II diabetesin combination with standard insulin therapy, in patients who havefailed to achieve adequate glucose control on insulin monotherapy.Proteosome Velcade ™ Proteosome inhibitors inhibitors PyrrolidineQuinopril ACE Inhibitors Ranibizumab Lucentis ™ For the treatment ofpatients with 27043 neovascular (wet) age-related macular degeneration.Rapamycin (MacuSight) Limus Immunophilin AMD (siroliums) BindingCompounds Rasburicase Elitek ™; Elitek ™ (Sanofi-SynthelaboAntihyperuricemic For treatment of hyperuricemia, reduces 168.11 Inc);Fasturtec ™ Agents elevated plasma uric acid levels (from chemotherapy)Reteplase Retavase ™ (Centocor); Retavase ™ Thrombolytic Agents Forlysis of acute pulmonary emboli, 54732 (Roche) intracoronary emboli andmanagement of myocardial infarction Retinal stimulant Neurosolve ™(Vitreoretinal Retinal stimulants AMD Technologies) Retinoid(s)Rituximab MabThera ™; Rituxan ™ Antineoplastic Agents For treatment ofB-cell non-Hodgkins 33078 lymphoma (CD20 positive) RNAI (RNAinterference of angiogenic factors) Rofecoxib Vioxx ™; Ceoxx ™; Ceeoxx ™(Merck Cyclooxygenase & Co.) Inhibitors Rosiglitazone ThiazolidinedionesRuboxistaurin Eli Lilly Protein Kinase C DME, diabetic peripheralretinopathy 469 (PKC)-b Inhibitor Salmon Calcimar ™; Miacalcin ™(Novartis) Antihypocalcemic For the treatment of post-menopausal 57304Calcitonin Agents; osteoporosis Antiosteporotic Agents; Bone DensityConservation Agents Sargramostim Immunex ™; Leucomax ™ (Novartis);Anti-Infective Agents; For the treatment of cancer and bone 46207Leukine ™; Leukine ™ (Berlex Antineoplastic Agents; marrow transplantLaboratories Inc) Immunomodulatory Agents SAR 1118 SARCodeImmunomodulatory Dry eye, DME, conjunctivitis Agent SDZ-RAD LimusImmunophilin Binding Compounds Secretin SecreFlo ™; Secremax ™,SecreFlo ™ Diagnostic Agents For diagnosis of pancreatic exocrine 50207(Repligen Corp) dysfunction and gastrinoma Selective inhibitor of thefactor 3 complement cascade Selective inhibitor of the factor 5complement cascade Semaxanib Tyrosine Kinase 238 Inhibitors SermorelinGeref ™ (Serono Pharma) Anabolic Agents; For the treatment of dwarfism,prevention 47402 Hormone Replacement of HIV-induced weight loss AgentsSerum albumin Megatope ™ (IsoTex Diagnostics) Imaging Agents Fordetermination of total blood and 39000 iodinated plasma volumes SF1126Semafore PI3k/mTOR Inhibition AMD, DME Sirolimus (MacuSight) LimusImmunophilin AMD reformulation Binding Compounds (rapamycin) siRNAmolecule (Quark Pharmaceuticals) siRNA molecule AMD synthetic, syntheticFTP-801i-14 Somatropin BioTropin ™ (Biotech General); Anabolic Agents;For treatment of dwarfism, acromegaly 71500 recombinant Genotropin ™(Pfizer), Humatrope ™ Hormone Replacement and prevention of HIV-inducedweight (Eli Lilly); Norditropin ™ (Novo Agents loss Nordisk); Nutropin ™(Genentech Inc.); NutropinAQ ™ (Genentech Inc.); Protropin ™ (GenentechInc.); Saizen ™ (Serono SA); Serostim ™; Serostim (Serono SA); Tev-Tropin ™ (GATE) Squalamine Streptokinase Streptase ™ (Aventis BehringerThrombolytic Agents For the treatment of acute evolving 90569 GmbH)transmural myocardial infarction, pulmonary embolism, deep veinthrombosis, arterial thrombosis or embolism and occlusion ofarteriovenous cannulae Sunitinib Tyrosine Kinase 398 Inhibitors TA106Taligen Complement Cascade AMD Inhibitor (Factor B) Tacrolimus LimusImmunophilin Binding Compounds Tenecteplase TNKase ™ (Genentech Inc)Thrombolytic Agents For treatment of myocardial 54732 infarction andlysis of intracoronary emboli Teriparatide Apthela ™; Forsteo ™;Forteo ™; Bone Density For the treatment of osteoporosis in men 66361Fortessa ™; Opthia ™; Optia ™; Conservation Agents and postmenopausalwomen who are at Optiah ™; Zalectra ™; Zelletra ™ high risk for having afracture. Also used to increase bone mass in men with primary orhypogonadal osteoporosis who are at high risk for fracture.Tetrathiomolybdate Thalidomide Celgene Anti-inflammatory, UveitisAnti-proliferative Thyrotropin Alfa Thyrogen ™ (Genzyme Inc) DiagnosticAgents For detection of residueal or recurrent 86831 thyroid cancerTie-1 and Tie-2 kinase inhibitors Toceranib Tyrosine Kinase 396Inhibitors Tositumomab Bexxar ™ (Corixa Corp) Antineoplastic Agents Fortreatment of non-Hodgkin's 33078 lymphoma (CD20 positive, follicular)TPN 470 analogue Trastuzumab Herceptin ™ (Genentech) AntineoplasticAgents For treatment of HER2-positive 137912 pulmonary breast cancerTriamcinolone Triesence ™ Glucocorticoid DME, For treatment ofinflammation 435 acetonide of the retina Troglitazone ThiazolidinedionesTumistatin Urofollitropin Fertinex ™ (Serono S.A.) Fertility Agents Fortreatment of female infertility 78296 Urokinase Abbokinase ™;Abbokinase ™ (Abbott Thrombolytic Agents For the treatment of105ulmonary 90569 Laboratories) embolism, coronary artery thrombosis andIV catheter clearance Vandetanib Tyrosine Kinase 475 InhibitorsVasopressin Pitressin ™; Pressyn ™ Antidiuretics; For the treatment ofenuresis, 46800 Oxytocics; polyuria, diabetes insipidus, VasoconstrictorAgents polydipsia and oesophageal varices with bleeding VatalanibTyrosine Kinase 347 Inhibitors VEGF receptor kinase inhibitor VEGF TrapAflibercept ™ (Regneron Genetically Engineered DME, cancer, retinal veinocclusion, 96600 Pharmaceuticals, Bayer HealthCare Antibodies choroidalneovascularization, delay AG) wound healing, cancer treatment VisualCycle (Acucela) Visual Cycle Modulator AMD Modulator ACU- 4229Vitamin(s) Vitronectin receptor antagonists Volociximab Ophthotechalpha5beta1 Integrin AMD Inhibitor XL765 Exelixis/Sanofi-AventisPI3k/mTOR Inhibition AMD, DME

What is claimed is:
 1. An exchange device to inject a therapeutic agentinto an ocular implant that is at least partially implanted in an eye,the exchange device comprising: a connector configured to reversiblycouple to a syringe; a needle having a proximal end region fixedlycoupled to the connector, the needle defining an injection lumenconfigured for injecting a therapeutic agent into the ocular implantthrough a distal opening of the needle; a receiver container coupled tothe connector; and an outer sheath coupled to a distal end region of thereceiver container, the outer sheath comprising: a wall defining anoutlet lumen between an inner diameter of the wall and an outer diameterof the needle, the outlet lumen in fluid communication with the receivercontainer; a distal tip; and a plurality of openings extending throughthe wall of the outer sheath into the outlet lumen, wherein the receivercontainer is fixedly coupled to the connector such that the outer sheathis positioned around at least a portion of the needle and the distalopening of the needle is positioned distal to the distal tip of theouter sheath, and wherein application of positive pressure through theinjection lumen by the syringe during injection of the therapeutic agentinto the ocular implant displaces, with at least partial separation fromthe injected therapeutic agent, pre-existing liquid in the ocularimplant into the receiver container via the outlet lumen.
 2. A device asin claim 1, wherein the distal tip of the outer sheath tapers such thatat least a portion of the distal tip of the sheath contacts an outersurface of the needle.
 3. A device as in claim 1, wherein at least aportion of the distal tip of the outer sheath is spaced from an outersurface of the needle.
 4. A device as in claim 1, wherein the receivercontainer is removable from the connector.
 5. A device as in claim 1,wherein the plurality of openings are positioned circumferentially aboutthe outer sheath.
 6. A device as in claim 1, further comprising a stopcoupled to the distal end region of the receiver container such that theneedle and the sheath extend through the stop, the stop having a surfaceconfigured to engage a tissue of the patient.
 7. A device as in claim 6,wherein the plurality of openings of the sheath are positioned distal tothe receiver container and are separated distally from the stop by adistance from about 0.25 mm to about 2 mm.
 8. A device as in claim 7,wherein the plurality of openings are located at a plurality ofcircumferential locations around a longitudinal axis of the sheath.
 9. Adevice as in claim 7, wherein the plurality of openings of the sheathare located at a plurality of axial locations along a longitudinal axisof the sheath.
 10. A device as in claim 1, wherein the distal tip of thesheath tapers at an angle of no more than about 20 degrees to alongitudinal axis of the sheath.
 11. A device as in claim 1, wherein thereceiver container comprises a penetrable barrier configured to bepenetrated in order to draw a sample from the receiver container.
 12. Adevice as in claim 1, wherein the therapeutic agent has a first fluiddensity and the pre-existing liquid has a second fluid density that isless than the first fluid density.
 13. A device as in claim 1, whereinthe therapeutic agent has a first fluid viscosity and the pre-existingliquid in the ocular implant has a second fluid viscosity that is lessthan the first fluid viscosity.
 14. A device as in claim 1, wherein theconnector comprises a Luer connector, a pressure fit connector, anon-standard connector, or a lock and key mechanism.
 15. A device as inclaim 1, wherein the connector comprises a lock and the syringecomprises a key configured to unlock the lock of the connector forming alock and key mechanism to limit access to the device.
 16. A device as inclaim 1, wherein the therapeutic agent flows from the syringe throughthe injection lumen when the connector is reversibly coupled to thesyringe and positive pressure is applied by the syringe.
 17. A device asin claim 1, wherein a predetermined amount of the therapeutic fluidinjected into the ocular implant corresponds to no more than about twicea volume of the ocular implant.
 18. A device as in claim 17, wherein thevolume of the ocular implant is no more than about 100 uL.
 19. A deviceas in claim 17, wherein the syringe is pre-filled with the predeterminedamount of the therapeutic fluid.
 20. A device as in claim 1, wherein theneedle is 33 gauge and a pressure generated within the needle duringinjection is no greater than about 85 psi.